KR100671275B1 - Finely divided eplerenone composition - Google Patents

Abstract

The present invention relates to oral pharmaceutical compositions useful as aldosterone receptor blockers, comprising from about 10 mg to about 1000 mg of active finely divided eplerenone and one or more carrier materials.

Description

Finely divided Eplerenone composition {MICRONIZED EPLERENONE COMPOSITIONS}

The present invention relates to a pharmaceutical composition comprising a complex eplerenone as an active ingredient, more particularly a composition comprising finely divided eplelenone, a treatment comprising administering such a pharmaceutical composition to a patient in need thereof. Methods and the use of such compositions in the manufacture of a drug.

Compound Methyl Hydrogen 9,11α-Epoxy-17α-hydroxy-3-oxopregan-4-ene-7α, 21-dicarboxylate, γ-lactone (also referred to herein as eplerenone) are first disclosed in US Patents. 4,559,332 (Grove et al.), Which discloses and claims a process for the preparation of such compounds with a class of 9,11-epoxy steroid compounds and salts thereof. These 9,11-epoxy steroid compounds have been described as aldosterone antagonists that can be administered in therapeutically effective amounts to treat pathological conditions associated with hyperaldehyde, such as hypertension, cardiac disability and cirrhosis. US Pat. No. 4,559,332 contains general references for the formulation of 9,11-epoxy steroid compounds, such as tablets and capsules.

WO 98/25948 of Ng et al. Later disclosed a method for the synthetic preparation of 9,11-epoxy steroid compounds and salts thereof of a similar class comprising eplerenones. US Pat. No. 4,559,332 and WO 98/25948 are all incorporated herein by reference.

Eplerenone has the following general formula (I):

Corresponds to the structure of.

Spironolactone, another 20-spiroxane-steroid, active as an aldehyde antagonist, is typically useful for treating hypertension. Spironolactone is represented by the following formula II:

Corresponds to the structure of. Spironolactone, however, exhibits anti-androgen activity, which can result in mild premenstrual activity resulting in female breast and sexual inability in men and irregular menstruation in women. Commercial formulations of spironolactone (sold under the name Aldacton ^™ ) are particularly useful as carrier materials, potassium sulfonate dihydrate as a diluent, yellow starch as a dispersant, povidone K-30 as a binder, magnesium stearate as a lubricant, and fragrances, Spironolactone 25, 50 or 100 mg in a substrate comprising a pigment and a coating comprising hydroxypropyl methylcellulose and polyethylene glycol 400.

Jay as a gas wave. Steroid Research, 22 (1B): 223-227 (1989) announced the use of spironolactone and epoxymexrenone in receptor binding studies. Such materials can be used in vivo to study the release of sodium in the urine, together with spironolactone in commercial formulations of 5 micron particle size and epoxymexerenone of 20 micron particle size in non-formulated compositions.

There is a need for the development of additional active aldosterone antagonists, such as eplerenone, which interact minimally with other steroid receptors, such as glucocorticoids, progestins and androgen steroid receptor systems, and / or provide more coverage of treatment. There is also a need for an eplerenone composition that provides an immediate form of eplerenone. The following study discloses an eplerenone composition that helps to meet such needs.

Effective administration of eplerenone to a patient has been difficult due to its low solubility and low compressibility as well as its other physical and chemical properties. However, it has been found that pharmaceutical compositions comprising finely divided eplerenones and pharmaceutically acceptable carriers can effectively deliver therapeutically desirable amounts of such compounds to a patient. In addition, the unique binding of the carrier with finely divided eplerenones has been found to provide even better dissolution properties. This combination of active compound and carrier material has been found to possess improved bioavailability, chemical stability, physical stability, dissolution profile, disintegration time, safety, as well as other improved pharmacokinetic, chemical and / or physical properties. The present invention includes such pharmaceutical compositions, unit dosage forms based thereon, and methods and uses for the preparation of both.

Pharmaceutical compositions comprising daily doses of finely divided eplerenone and a pharmaceutically acceptable carrier as active ingredients have been found to be unique compositions that exhibit excellent performance as aldosterone receptor blockers. Such pharmaceutical compositions exhibit good activity, efficacy, safety and therapeutic effectiveness in this dosage range. Such a composition is sufficient to supply prolonged blocking of the aldosterone receptor and thus provides the desired therapeutic benefit, while supplying the eplerenone to the patient at a dose that maintains a safe erasure time. Unwanted side effects such as gastrointestinal irritation, antiandrogen and premenstrual activity are also minimized with the pharmaceutical compositions of the present invention.

Such pharmaceutical compositions are beneficial for use in blocking aldosterone receptors, and in particular pharmacological action can increase sodium and water release with coexisting potassium-deficient effects. Such compositions include, in particular, heart failure; Hypertension (especially mild treatment of moderate hypertension); Edema associated with liver disability; Post-myocardial infarction; Cirrhosis; Seizure prevention; And cardiovascular diseases such as pulse rate reduction for patients with fast pulse rates. Such pharmaceutical compositions exhibit, among other features, improved selectivity to (iv) aldosterone receptors, (ii) reduced binding affinity for progesterone and androgen receptors, and (iii) reduced interference from plasma proteins.

Such compositions are useful for the treatment of humans, as well as for the veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents and the like. More preferred non-human animals include horses, dogs, and cats.

Unformulated eplerenones administered in capsule form are not well absorbed into the stomach. Therefore, a suitable eplerenone dosage form is required. The pharmaceutical compositions of the present invention provide such dosage forms and exhibit one or more excellent properties for other compositions, including unformulated eplerenone and / or eplerenone. Such excellent properties include one or more of the following:

(1) improved bioavailability;

(2) improved solubility of the pharmaceutical composition;

(3) reduced disintegration time for immediate release oral dosage forms;

(4) reduced dissolution time for immediate release oral dosage forms;

(5) improved dissolution profile for the adjusted release oral dosage form;

(6) reduced tablet breakage;

(7) increased tablet strength;

(8) improved safety for oral dosage forms;

(9) reduced moisture content and / or hygroscopicity for oral dosage forms;

(10) improved composition wettability;

(11) improved particle size distribution of eplerenones;

(12) improved composition compressibility;

(13) improved composition flowability;

(14) improved chemical stability of the final oral dosage form;

(15) improved physical stability of the final oral dosage form;

(16) reduced tablet size;

(17) improved mixing uniformity;

(18) improved dose uniformity;

(19) increased granule density for the wet granulation composition;

(20) reduced moisture demand for wet granular conditions;

(21) reduced wet granular state time; And / or

(22) Reduced drying time for wet granule mixtures.

Differentiated Eplerenone

Although the present pharmaceutical compositions are effective for a wide range of particle sizes for the initial eplerenone starting materials used in the compositions, particle size reduction to a D ₉₀ particle size of about 25 to about 400 microns may result in an increase in the eplerenone bioavailability. It has been found to be able to improve. Eplerenone particles having a D ₉₀ particle size of about 25 to about 400 microns will be referred to herein as finely divided or finely divided eplerenone particles.

Accordingly, the D ₉₀ particle size (ie, at least 90% of the particles) of the eplerenone used as starting material in the composition is about 400 microns or less, preferably 200 microns or less, and more preferably about 150 microns Or less, even more preferably about 100 microns or less and even more preferably 90 microns or less. Particularly preferred D ₉₀ particle sizes are about 30 to about 110 microns, more particularly about 30 to 50 microns. In another preferred embodiment, the particularly preferred D ₉₀ particle size is about 50 to about 150 microns, more particularly about 75 to about 125 microns. Epulenone finely divided to such a size also generally exhibits a D ₁₀ particle size of less than 10 microns. For example, as described in Example 30, reducing the D ₉₀ particle size of the starting material eplerenone from about 220 microns to about 90 microns can substantially improve the bioavailability of the pharmaceutical composition.

Eplerenone Dose of Pharmaceutical Composition

The pharmaceutical composition of the present invention comprises about 10 mg to about 1000 mg of finely divided eplerenone. Preferably the pharmaceutical composition comprises about 20 mg to about 400 mg, more preferably about 25 mf to about 200 mg, and even more preferably about 25 mg to about 150 mg of finely divided eplerenone.

Treatment of special conditions and disorders

Pharmaceutical compositions of the invention are useful where administration of the aldosterone receptor blocker is indicated. Such compositions include heart failure; Hypertension (especially mild treatment of moderate hypertension); Edema associated with liver disability; Post-myocardial infarction; Cirrhosis; Seizure prevention; And cardiovascular diseases such as heart rate reduction for patients exhibiting accelerated heart rate.

For the treatment of heart failure, the pharmaceutical composition is preferably supplied with a daily dose of about 25 mg to about 200 mg, more preferably about 25 mg to about 75 mg, even more preferably about 50 mg of eplerenone. A daily dose of about 0.33 to 2.67 mg / kg (based on an average body weight of about 75 kg) relative to body weight is preferred, preferably about 0.33 to about 1.00 mg / kg, most preferably 0.67 mg / kg. The daily dose may be administered in one to four doses per day, with one dose per day being preferred.

For the treatment of hypertension, the pharmaceutical composition is preferably supplied with a daily dose of eplerenone at about 50 mg to about 300 mg, more preferably about 50 mg to about 150 mg, even more preferably about 100 mg. A daily dose of 0.67 to 4.00 mg / kg, preferably about 0.67 to about 2.00 mg / kg and most preferably about 1.33 mg / kg, for body weight is suitable. The daily dose may be administered in one to four doses per day, with one dose per day being preferred.

In order to treat edema associated with hepatic disability, the pharmaceutical composition is preferably supplied with a daily dose of eplerenone at about 50 mg to about 500 mg, more preferably about 100 mg to about 400 mg, even more preferably about 300 mg. . A daily dose of 0.67 to 6.67 mg / kg, preferably about 1.33 to about 5.33 mg / kg and most preferably about 4.00 mg / kg, for body weight is suitable. The daily dose may be administered in one to four doses per day, with one dose per day being preferred.

The pharmaceutical compositions of the present invention have been found to provide therapeutic effects as human aldosterone receptor blockers over about 12 to 24 hours, preferably about 24 hours after oral administration.

In general, the pharmaceutical compositions of the present invention provide a daily dose of aldosterone sufficient to cause an increase in human aldosterone concentration and serum renin over about 12 to 24 hours, preferably 24 hours after oral administration. In particular, such compositions provide a daily dose of eplerenone sufficient to cause an average increase in serum renin concentrations over about 12 to 24 hours, preferably about 24 hours, after at least about 10% composition ingestion. Similarly, such compositions provide a daily dose of eplerenone sufficient to cause an average increase in serum aldosterone concentration over about 12 to 24 hours, preferably about 24 hours, after at least about 50% composition ingestion.

The pharmaceutical compositions of the present invention also contain a daily dosage of sufficient to bring about an average increase in the log ₁₀ (sodium / potassium) ratio of human urine over about 12 to 24 hours, preferably about 24 hours after ingestion of the composition. It was found to supply fullerenone.

The pharmaceutical compositions of the present invention also contain a daily dose of Eppler sufficient to cause an average decrease in diastolic blood pressure in the human body over an interval of about 12 to 24 hours, preferably about 24 hours after ingesting at least about 5% of the composition. It was found to supply Lennon.

Unit capacity

Dosage unit forms of the pharmaceutical composition will generally include, for example, 10, 20, 25, 37.5, 50, 75, 100, 125, 150, 175, 200, 250, 300, 350 or 400 mg of eplerenone Can be. Dose unit forms may be selected to suit the desired frequency of administration used to achieve the specified daily dose. The amount and condition of the unit dosage form of the pharmaceutical composition administered or the dosage regimen for treating the disorder depends on a variety of factors including the age, weight, sex and condition or severity of the disorder, the route and frequency of administration, and are therefore known. It can be as diverse as it is.

However, it has been found that the efficacy of the required daily doses of the pharmaceutical compositions of the present invention does not differ substantially from administration once daily compared to administration twice daily for the compositions described in this application. Without being bound by theory, it is assumed that the compositions of the present invention deliver an amount of eplerenone sufficient to inhibit the extended genomic response caused by aldosterone binding to the aldosterone receptor site. Interference of aldosterone binding by eplerenones interferes with aldosterone-induced gene production synthesis, which results in an extended cycle of functional aldosterone receptor blockage that does not require sustained plasma eplerenone concentrations. Thus, administration once a day is preferred for such tablets for convenient administration.

Preparation of Eplerenone

Eplerenones of the novel pharmaceutical compositions of the present invention can be prepared using the methods described in US Pat. No. 4,559,332 to Grove et al. And WO 98/25948 to Engie et al., In particular, Scheme 1 described in Eng. WO 98/25948. And the two patents are incorporated by reference.

Form of pharmaceutical composition

The pharmaceutical compositions of the present invention comprise finely divided eplerenones associated with one or more non-toxic, pharmaceutically-acceptable carriers, excipients and / or adjuvants (collectively referred to herein as "carrier materials"). Carrier materials are acceptable in that they can coexist with other components of the composition and are not detrimental to acceptance. The pharmaceutical compositions of the present invention may be adapted for administration by any suitable route by the selection of suitable carrier materials and by the dose of eplerenone effective for the intended treatment. For example, such compositions may be prepared in a form suitable for oral, intravenous, intraperitoneal, subcutaneous, intramuscular (IM) or rectal administration. Thus, the carrier material employed can be solid or liquid, or both, for example from about 1% to about 95%, preferably from about 10% to about 75%, more preferably by the finely divided eplerenone weight. Preferably, the compound is formulated into a unit-dose composition, such as a tablet, which may comprise from about 20% to about 60%, even more preferably from about 20% to about 40%. Such pharmaceutical compositions of the present invention may be prepared by any of the known formulations which consist essentially of mixing the components.

Oral administration

For oral administration, the pharmaceutical composition may comprise a desired amount of finely divided eplerenones, for example tablets, hard or soft capsules, courtyards, cassienans, administrable powders, granules, suspensions, elixirs , Liquid or any other form rationally adopted for oral administration. Such pharmaceutical compositions are preferably prepared in the form of discrete dosage units comprising a predetermined amount of eplerenone, such as a tablet or capsule. Such oral dosage forms may further comprise, for example, a buffer. Tablets, pills and the like can be prepared with an enteric coating. Unit dose tablets or capsules are preferred.

Pharmaceutical compositions suitable for oral (under the tongue) administration include, for example, a courtyard comprising eplerenone in a flavored base such as sucrose, acacia or tragacanth and an inert base such as gelatin, glycerin, sucrose and acacia. Includes pastilles comprising eplelenone within.

Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs, including inert diluents commonly used in the art. Such compositions may also include, for example, wetting agents, emulsifiers and suspending agents, and sweeteners, spices, and fragrances.

Examples of suitable liquid dosage forms include water-soluble derivatives of β-cyclodextrin, such as eplelenone and β-cyclodextrin or sulfobutyl ether β-cyclodextrin; Heptakis-2,6-di-O-methyl-β-cyclodextrin; Hydroxypropyl-β-cyclodextrin; And aqueous solutions containing dimethyl-β-cyclodextrin and the like.

Administration by injection

The pharmaceutical compositions of the invention may also be administered by injection (intravenously, intramuscularly, subcutaneously or eruption). Such injectable compositions may employ, for example, saline, dextrose, or water as suitable carrier materials. The pH value of the composition can be adjusted with a suitable acid, base or buffer if necessary. Suitable swelling agents, dispersants, wetting or suspending agents, including mannitol and polyethylene glycol (such as PEG 400) may also be included in the compositions. Suitable injection compositions may also include eplelenone in the injection vial. Aqueous solutions may be added to dissolve the composition prior to injection.

Rectal administration

The pharmaceutical compositions can be administered in the form of suppositories or the like. Formulation of such rectal comprises, for example, eplerenone finely divided in total amount from 0.075 to 30% w / w, preferably 0.2 to 20% w / w and most preferably 0.4 to 15% w / w. It is preferable. Carrier materials such as cocoa butter, theobroma oil, and other oils and polyethylene glycol suppository bases can be used in such compositions. If desired, other carrier materials may also be employed, such as coatings (eg, hydroxypropyl methylcellulose film coatings) and disintegrants (eg, croscarmellose sodium and cross-linked povidone).

As pointed out above, such pharmaceutical compositions may be prepared by any suitable preparation, including the step of bringing the related eplereron and carrier material or carrier materials. Generally, the composition is prepared by uniformly and immediately mixing the active compound with a liquid or finely divided solid carrier, or both, and then molding the product, if necessary. For example, a tablet may be made by compressing or molding a powder or granules of the compound with any one or more accessory ingredients. Compressed tablets may be prepared by extruding, in a suitable machine, a compound in free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent and / or surfactant / dispersant (s). Molded tablets may be prepared by molding inert liquid diluent and moistened powder compound with a suitable machine.

Carrier material

As noted above, for therapeutic purposes, the pharmaceutical compositions of the present invention comprise a desired amount of finely divided eplerenone in combination with one or more pharmaceutically-acceptable carrier materials suitable for the indicated route of administration. Oral dosage forms of the pharmaceutical compositions of the present invention are preferably mixed with one or more carrier materials selected from the group consisting of diluents, disintegrants, binders and adhesives, wetting agents, glidants, semi-adhesives and / or other carrier materials. Positive finely divided eplerenones. Such capsules or tablets may be in the form of immediate release capsules or tablets, or may include controlled-release preparations, such as, for example, which may be supplied as a dispersion of eplerenone in hydroxypropyl methylcellulose.

Injectable dosage forms are preferably adapted for injection of injectables. Preferably, such dosage forms are water-soluble or suspended in or dissolved in water, such as eplelenone, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride and / or various buffers. Elurenone finely divided into non-aqueous isotonic sterile injectable solutions or suspensions. Such solutions and suspensions may be prepared from sterile powders or granules having one or more of the carriers or diluents described above for use in formulating oral administration.

The choice and combination of carrier materials used in the pharmaceutical compositions of the present invention may in particular be effective, bioavailability, scavenging time, stability, compressibility, stability, dissolution profile, disintegration profile and / or other pharmacokinetics of the eplerenone and the carrier material. Provided are compositions that exhibit improved performance with respect to chemical, chemical and / or physical properties. The carrier material preferably has a wetting property that is soluble in water or dispersible in water and that compensates for the low water solubility and hydrophobicity of the eplerenone. Where the composition is formulated into tablets, the binding of the selected carrier material in particular provides tablets that can exhibit improved dissolution and disintegration profile, hardness, crushing force, and / or easily cracking.

diluent

The pharmaceutical composition of the present invention may optionally comprise one or more diluents as carrier material. Suitable diluents include lactose USP; Lactose USP, anhydride; Lactose USP, dried spray; Starch USP; Starch directly compressible; Mannitol USP; Sorbitol; Dextrose monohydrate; Microcrystalline cellulose NF; Dibasic calcium phosphate dihydrate NF; Sucrose-based diluent; Powdered sugar; Monobasic calcium sulfate monohydrate; Calcium sulfate dihydrate NF; NF on calcium lactate trihydrate granules; Dexrate NF (eg, Emdex ^TM ); Sellers Tab ^TM; Textloss (eg, Cerrose ^™ ); Inositol; Hydrolyzed cereal solids such as Maltron ^™ and Mor-Rex ^™ ; Amylose; Lexel ^TM ; Powdered cellulose (eg, Elsema ^™ ); Calcium carbonate; Glycine; Bentonite; Diluents such as polyvinylpyrrolidone and the like, individually or in combination.

Microcrystalline cellulose (eg Avicel ^® PH 101) and lactose are preferred diluents, either individually or in combination (when both diluents are present). Both diluents are chemically coexistable with microcrystalline eplerenone. Extragranular microcrystalline cellulose (ie, microcrystalline cellulose added to the wet granulated composition after the drying step) is added to intragranular microcrystalline cellulose (ie, microcrystalline cellulose added to the composition during or before the wet granulation step). Additive use may be used to improve tablet strength and / or disintegration time. Especially preferred are lactose, in particular lactose monohydrate. Lactose generally provides pharmaceutical compositions having the property of drying at a suitable eplelenone release rate, stability, pre-compressive flow capacity and relatively low diluent cost.

Disintegrant

The pharmaceutical compositions of the present invention may optionally comprise one or more disintegrants as carrier materials, especially for tablet formulation. Suitable disintegrants include starch; Sodium starch glycorate; Clay (nongum ^TM HV, etc.); Cellulose (purified cellulose, methylcellulose and sodium carboxymethylcellulose, and carboxymethylcellulose); Alginate; Pregelatinized corn starch (National ^TM 1551 and National ^TM 1550); Crospovidone USP NF; Disintegrating agents such as gums (agar, guar, locust bean, Karaya ^TM , pectin, and tragacanth) may be included alone or in combination. Disintegrants may be added during all suitable steps in the preparation of the pharmaceutical composition, in particular during the lubrication step before granulation or before compression. The pharmaceutical compositions of the present invention may contain one or more disintegrants in the range of about 0.5% to about 30%, preferably about 1% to about 10%, and more preferably about 2% to about 6% of the total weight of the composition. Include.

Croscarmellose sodium is a preferred disintegrant for tablet formulation in the range of about 1% to about 10%, preferably about 2% to about 6%, and more preferably about 5% by weight of the composition.

Binders and adhesives

The pharmaceutical composition of the present invention may optionally comprise one or more binders or adhesives as the carrier material. Binders and adhesives allow the powder to follow normal procedures such as formulation, lubrication, compression, and packaging, while tablets disintegrate upon ingestion and preferably impart sufficient adhesion to the composition to dissolve. Suitable binders and adhesives include acacia; Tragatans; Crosses; gelatin; Glucose; Starch; Cellulose materials such as methyl cellulose and sodium carboxymethyl cellulose (eg, tyros ^TM ); Alginic acid and alginate; Magnesium aluminum silicate; Polyethylene glycol; Guar gum; Polysaccharide acids; Bentonite; Polyvinylpyrrolidone (povidone); Polymethacrylates; Hydroxypropyl methylcellulose (HPMC); Hydroxypropyl cellulose (Klucel ^™ ); Ethyl cellulose (etocell ^TM ); Binders and adhesives such as pregelatinized starch (National ^TM 1511 and starch 1500, etc.) alone or in combination. The pharmaceutical composition may comprise one or more binders and / or adhesives in the range of about 0.5% to about 25%, preferably about 0.75% to about 15%, and more preferably about 1% to about 10% of the total weight of the composition. It includes.

Hydroxypropyl methylcellulose is the preferred binder used to impart adhesion to the powder mix of the eplerenone formulation. The composition comprises hydroxypropyl methylcellulose as a binder in the range of about 0.5% to about 10%, more preferably about 1% to about 8%, and even more preferably about 2% to about 4% of the total weight of the composition. It is preferable to include. Low molecular weight hydroxypropyl methylcellulose having a viscosity of about 2 cps to about 8 cps can generally be used, nevertheless a viscosity of about 2 cps to about 6 cps is preferred, and a viscosity of about 2 cps to about 4 cps is particularly preferred. The methoxy content of hydroxypropyl methylcellulose is generally about 15% to about 35%, while the hydroxypropyl content generally amounts to about 15%, preferably about 2% to about 12%.

Humectant

Eplerenone is very insoluble in aqueous solutions even when finely divided. Accordingly, the pharmaceutical compositions of the present invention may optionally comprise one or more wetting agents as carrier materials, especially for tablet formulations. Such humectants desirably maintain eplerenone in solution and improve the bioavailability of the pharmaceutical composition. Suitable humectants include oleic acid; Glyceryl monostearate; Sorbitan monooleate; Polyoxyethylene sorbitan mono-oleate; Polyoxyethylene sorbitan monolaurate; Sodium oleate; And humectants, such as sodium lauryl sulfate, alone or in combination. The wetting agent is preferably anionic surfactant. The pharmaceutical composition comprises at least one humectant from about 0.1% to about 15%, preferably from about 0.25% to about 10%, and more preferably from about 0.5% to about 5% of the total weight of the composition.

Sodium lauryl sulfate is the preferred humectant for tablet formulations. The composition of the present invention comprises sodium lauryl sulfate as a wetting agent at about 0.25% to about 7%, more preferably about 0.4% to about 4%, and even more preferably about 0.5% to about 2% of the total weight of the composition. Preferably.

Lubricant

The pharmaceutical compositions of the present invention optionally comprise one or more glidants and / or glidants as carrier material. Suitable glidants and / or glidants include glyceryl behenethyr (compritol ^™ 888); Stearic acid metal salts (eg, magnesium stearate, calcium, and sodium salts); Stearic acid; Hydrogenated vegetable oils (eg, Sterotex ^™ ); Talc; Wax; Stearowet ^TM ; Boric acid; Sodium benzoate and sodium acetate; Sodium chloride; DL-leucine; Polyethylene glycols (eg Carbowax ^™ 4000 and Carbowax ^™ 6000); Sodium oleate; Sodium benzoate; Sodium acetate; Sodium lauryl sulfate; Sodium stearyl fumarate (PruvRM); And glidants and / or glidants such as magnesium lauryl sulfate, alone or in combination. The pharmaceutical composition comprises one or more lubricants from about 0.1% to about 10%, preferably from about 0.2% to about 8%, and more preferably from about 0.25% to about 5% of the total weight of the composition.

Magnesium stearate is the preferred glidant used to reduce friction between the device and granules during compression.

Semi-adhesive or glidant

The pharmaceutical composition of the present invention may optionally comprise one or more semi-adhesives or glidants as carrier material. Suitable semi-adhesives or glidants include, alone or in combination, semi-adhesives such as talc, corn starch, cap-o-silTM, siloidsTM, DL-leucine, sodium lauryl sulfate, and metallic stearate. . The pharmaceutical composition comprises at least one semi-adhesive or glidant from about 0.1% to about 15%, preferably from about 0.25% to about 10%, and more preferably from about 0.5% to about 5% of the total weight of the composition.

Talc is a preferred semi-adhesive or glidant used to reduce the agent adhered to the device surface and also to reduce the static electricity in the mix. The composition preferably comprises talc from about 0.1% to about 10%, more preferably from about 0.25% to about 5%, and even more preferably from about 0.5% to about 2% of the total weight of the composition.

Other carrier materials (pigments, flavors and sweeteners, etc.) and dosage forms are known in the pharmaceutical art and can be used in the formulation of the pharmaceutical compositions of the invention. Tablets may or may not be coated.

In one embodiment of the invention, the pharmaceutical composition comprises a desired amount of finely divided eplerenone and one or more cellulosic carrier materials. "Cellulosic carrier material" means cellulose or clarified cellulose; Microcrystalline cellulose; And cellulose derivatives such as alkyl celluloses and derivatives and salts thereof (eg, methylcellulose, sodium carboxymethylcellulose, carboxymethylcellulose, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and the like). Preferably, the at least one carrier material is a cellulosic material selected from the group consisting of C ₁ -C ₆ -alkyl celluloses and their derivatives and salts. Even more preferably, this cellulosic material is selected from the group consisting of hydroxyalkyl alkylcelluloses and their derivatives and salts. Even more preferably such cellulosic material is selected from the group consisting of hydroxy (C ₂ -C ₄ -alkyl) (C ₁ -C ₄ -alkyl) celluloses and their derivatives and salts.

Such pharmaceutical compositions comprising a desired amount of finely divided eplerenone and one or more cellulosic carrier materials preferably further comprise one or more carrier materials selected from diluents, disintegrants, binders, wetting agents, glidants and semi-adhesives. Do. More preferably, such pharmaceutical composition comprises at least one carrier material selected from the group consisting of lactose, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl methylcellulose, sodium lauryl sulfate, magnesium stearate and talc. Even more preferably, such pharmaceutical compositions comprise lactose monohydrate, microcrystalline cellulose, croscarmellose sodium and hydroxypropyl methylcellulose. Even more preferably, such pharmaceutical compositions further comprise one or more carrier substances sodium lauryl sulfate, magnesium stearate and talc.

Each of the pharmaceutically acceptable carrier materials described in the above examples may be optionally replaced with other suitable carrier materials, if desired. Acceptable substituted carrier materials are chemically coexistable with eplerenone and other carrier materials. Although other diluents, disintegrants, binders and adhesives, wetting agents, glidants and / or semi-binders or glidants may be employed, however, finely divided eplerenone, lactose, microcrystalline cellulose, croscarmellose sodium, and hydride Pharmaceutical compositions comprising oxypropyl methylcellulose and, optionally, sodium lauryl sulfate, magnesium stearate, and / or talc have been found to possess superior binding of pharmacokinetic, chemical and / or physical properties over other compositions. .

In another embodiment, the pharmaceutical composition is:

About 1 to about 95 weight percent of finely divided eplerenone;

About 5 to about 99% by weight of a pharmaceutically acceptable diluent;

About 0.5 to about 30 weight percent of a pharmaceutically acceptable disintegrant; And

About 0.5 to about 25% by weight of a pharmaceutically acceptable binder.

Such pharmaceutical compositions optionally comprise about 0.25 to about 15 weight percent of a pharmaceutically acceptable wetting agent; About 0.1 to about 10 weight percent of a pharmaceutically acceptable lubricant; And from about 0.1 to about 15 weight percent of a pharmaceutically acceptable semi-binder.

As used herein, the term "% by weight" refers to the weight percent of a particular component based on the total weight of all components of the composition.

In another embodiment, the pharmaceutical composition comprises finely divided eplerenone and cellulosic carrier material, wherein the composition is an oral dosage form, preferably a tablet or capsule. Preferably, the composition further comprises one or more carrier materials selected from the group consisting of lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl methylcellulose, sodium lauryl sulfate, talc, and magnesium stearate. It is particularly preferable that the various components of the composition are present in the following amounts or weight fractions.

In another embodiment, the pharmaceutical composition is in the form of unit dose tablets or capsules.

In another embodiment, the pharmaceutical composition comprises an oral unit dose suitable for oral administration of the finely divided eplerenone and one or more carrier materials once or twice a day. Even more preferably, this pharmaceutical composition consists of finely divided eplelenone and lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl methylcellulose, sodium lauryl sulfate, talc, and magnesium stearate One or more carrier materials selected from the group. It is particularly preferred that the various components of the composition be present in the following amounts or weight fractions.

In another embodiment, the pharmaceutical composition provides a therapeutic effect as an aldosterone receptor blocker over an interval of about 12 to about 24 hours, preferably at least about 24 hours after oral administration to the required dose when orally administered to a human patient. Including finely divided eplerenone and one or more carrier materials. Even more preferably, such pharmaceutical composition is in the group consisting of finely divided composition and lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl methylcellulose, sodium lauryl sulfate, talc, and magnesium stearate At least one carrier material selected. It is particularly preferred that the various components of the composition be present in the following amounts or weight fractions.

In another embodiment, the pharmaceutical composition, when administered orally to a human patient, has a serum renin concentration over about 12 to about 24 hours, preferably about 24 hours, after a required amount of at least about 10% of the composition is consumed. Finely divided eplerenones and one or more carrier materials which result in an average increase in Even more preferably, this pharmaceutical composition is in the group consisting of finely divided eplelenone and lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl methylcellulose, sodium lauryl sulfate, talc, and magnesium stearate And at least one carrier material selected. It is particularly preferred that the various components of the composition be present in the following amounts or weight fractions.

In another embodiment, the pharmaceutical composition, when orally administered to a human patient, has a mean increase in serum aldosterone concentration over an interval of about 12 to 24 hours, preferably about 24 hours after ingesting the composition at least about 50%. Finely divided eplerenone and one or more carrier materials. Even more preferably, the pharmaceutical composition comprises one or more carrier materials selected from the group consisting of lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl methylcellulose, sodium lauryl sulfate, talc, and magnesium stearate. Includes finely divided eplerenones. It is particularly preferred that the various components of the composition be present in the following amounts or weight fractions.

In another embodiment, the pharmaceutical composition, when orally administered to a human patient, has an average decrease in diastolic blood pressure over a period of about 12 to 24 hours, preferably about 24 hours after ingesting the composition at least about 5%. And at least one carrier material and finely divided eplerenones which result in Even more preferably, the pharmaceutical composition comprises one or more carrier materials selected from the group consisting of lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl methylcellulose, sodium lauryl sulfate, talc, and magnesium stearate. Includes finely divided eplerenones. It is particularly preferred that the various components of the composition be present in the following amounts or weight fractions.

In another embodiment, the pharmaceutical composition has a log ₁₀ (sodium / potassium) ratio of urine over an interval of about 12 to about 24 hours, preferably about 24 hours after ingestion of the composition when orally administered to a human patient. Finely divided eplerenones and one or more carrier materials which result in an average increase in Even more preferably, such pharmaceutical composition comprises at least one carrier material selected from the group consisting of lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl methylcellulose, sodium lauryl sulfate, talc and magnesium stearate. And finely divided eplerenones. It is particularly preferred that the various components of the composition be present in the following amounts or weight fractions.

Immediate release formulation

Oral delivery of a pharmaceutical composition of the present invention may include immediate release compositions as well as adjusted release compositions. Preferably the pharmaceutical composition is in the form of an immediate release tablet or capsule. The immediate release composition may contain an amount sufficient to supply a desired daily dose of eplerenone, ie, about 10 mg to about 1000 mg, more preferably about 20 mg to about 400 mg, even more preferably about 25 mg to about 200 mg, even more preferably about Finely divided eplerenone in an amount from 25 mg to about 150 mg, even more preferably from about 50 mg to about 100 mg. Immediately once daily release tablets or capsules contain, for example, about 50 mg to about 100 mg of eplerenone. Preferably, the same batch can be used to make tablets (or capsules) of different strength by compressing the formulation to different tablet sizes (or by encapsulating the formulation in different capsule sizes or by weighing different capsule fill weights). Although the amount of eplerenone in such novel compositions is preferably within the ranges described above, the formulations may also be useful for administration of the amount of eplerenone outside the range of the modified dose.

Dissolution profile

The composition of the present invention has about 50% of finely divided eplerenone dissolved in vitro in about 15 minutes, more preferably at least about 80% of eplerenone is dissolved in vitro within about 30 minutes, even more preferably Is an immediate release composition in which at least about 90% of the eflerenone is dissolved in vitro within about 4 minutes using 1% sodium dodecyl sulfate (SDS) in water with a dissolution medium at 37 ° C. in the dissolution evaluation described below. More preferably, 0.1 N HCl in water at 37 ° C. is the in vitro dissolution medium in the evaluation, about 50% of the finely divided eplerenone dissolves in about 20 minutes, about 80% dissolves in about 45 minutes, and at least about 90% Dissolves in about 90 minutes. More preferably, about 50% of the finely divided eplerenones dissolve within about 15 minutes, about 80% within about 30 minutes, and at least about 90% within about 45 minutes.

Disintegration Profile

The carrier material for the immediate release composition is preferably selected to provide a disintegration time within about 30 minutes, preferably within about 20 minutes, more preferably within about 18 minutes, even more preferably within about 14 minutes.

Granule Particle Size and Fluidity

Although the pharmaceutical composition of the present invention may be prepared by, for example, direct encapsulation or direct compression, it is preferably wet granulated before encapsulation or compression. Wet granules in particular permeate additives into the composition to result in improved flowability, improved compression properties, and easier metering or weight distribution of the final composition. The average particle size of the granules preferably allows for convenient ingestion and composition, and for tablets, to form a directly compressible mixture that forms a pharmaceutically acceptable tablet. The desired trace and bulk density of the granules is normally from about 0.3 g / ml to about 1.0 g / ml, preferably from about 0.4 g / ml to about 0.8 g / ml.

burglar

For tablet formulations, an amount of pharmaceutical composition sufficient to produce a uniform batch of tablets should be purified by conventional production scale tablet machines at normal compression pressure (eg, about 1 kN to about 50 kN). Any tablet strength that is convenient in terms of handling, manufacturing, storage and ingestion can be adopted. Intensities in the range of about 3.5 kP to about 22 kP are generally acceptable, with about 3.5 kP to about 9 kP preferred for 25 mg tablets, about 5 kP to about 13 kP preferred for 50 mg tablets, About 8 kP to about 22 kP is preferred. However, the mixture is not compacted to the extent that there are subsequent difficulties in hydration when exposed to the gastric fluid.

Masson

For tablet formulations, tablet wear is less than or equal to about 0.8%, more preferably less than or equal to 0.4%.

Preferred Composition

Preferably, the pharmaceutical composition of the present embodiment;

About 1 to about 90 weight percent of finely divided eplerenone;

About 5 to about 90 weight percent of lactose;

About 5 to about 90 weight percent microcrystalline cellulose; And

About 0.5 to about 10 weight percent hydroxypropyl methylcellulose.

Such pharmaceutical compositions optionally comprise about 1 to about 10 weight percent of croscarmellose sodium; About 0.1 to about 7 weight percent sodium lauryl sulfate; About 0.1 to about 10 weight percent talc; And / or about 0.1 to about 10 weight percent magnesium stearate.

More preferably, the pharmaceutical compositions of this example are:

About 19 to about 40 weight percent of finely divided eplerenone;

About 32 to about 52 weight percent of lactose;

About 8 to about 28 weight percent microcrystalline cellulose;

About 1 to about 10 weight percent of croscarmellose sodium; And

About 1 to about 8 weight percent hydroxypropyl methylcellulose.

Such pharmaceutical compositions optionally comprise about 0.1 to 7 weight percent sodium lauryl sulfate; About 0.1 to about 10 weight percent talc; And about 0.1 to about 10 weight percent magnesium stearate. Preferably, the hydroxypropyl methylcellulose has a viscosity of about 2 cps to about 8 cps, more preferably about 2 cps to about 6 cps, as indicated above. The composition is preferably in the form of unit dose tablets.

Even more preferably, the pharmaceutical composition of this example is:

About 24 to about 35 weight percent of finely divided eplerenone;

About 37 to about 47 weight percent lactose;

About 13 to about 23 weight percent microcrystalline cellulose; And

About 2 to about 4 weight percent hydroxypropyl methylcellulose.

Such pharmaceutical compositions optionally comprise about 0.25 to about 4 weight percent sodium lauryl sulfate; About 0.1 to about 5 weight percent talc; And about 0.25 to about 5 weight percent magnesium stearate. Preferably, the hydroxypropyl methylcellulose has a viscosity of about 2 cps to about 6 cps as described above.

Even more preferably, the pharmaceutical composition of this example is:

About 28 to about 31 weight percent of finely divided eplerenone;

About 41 to about 43 weight percent lactose monohydrate;

About 17 to about 19 weight percent microcrystalline cellulose;

About 4.5 to about 5.5 weight percent croscarmellose sodium; And

About 2.5 to about 3.5 weight percent hydroxypropyl methylcellulose.

Such pharmaceutical compositions optionally comprise about 0.5 to about 1.5 weight percent sodium lauryl sulfate; About 0.5 to about 1.5 weight percent talc; And from about 0.25 to about 0.75 weight percent magnesium stearate. Preferably, the hydroxypropyl methylcellulose has a viscosity of about 2 cps to about 4 cps, as described above.

Even more preferably, the pharmaceutical composition of this example is in the form of a coated or uncoated unit dose tablet, wherein the uncoated tablet or coated tablet before coating is:

About 29.4% finely divided eplerenone;

About 42% lactose;

About 18.1% microcrystalline cellulose;

About 5% by weight of croscarmellose sodium;

About 3% hydroxypropyl methylcellulose;

About 1% sodium lauryl sulfate;

About 1% talc; And

About 0.5% by weight magnesium stearate.

In another embodiment, the pharmaceutical compositions of this example are:

About 20 mg to about 110 mg of finely divided eplerenone;

About 30 mg to about 150 mg of lactose;

About 10 mg to about 70 mg of microcrystalline cellulose; And

About 1 mg to about 15 mg of hydroxypropyl methylcellulose.

Such pharmaceutical compositions optionally comprise about 1 mg to about 25 mg of croscarmellose sodium; About 0.25 mg to about 5 mg of sodium lauryl sulfate; Talc of about 0.5 mg to about 5 mg; And about 0.5 mg to about 3 mg of magnesium stearate. Preferably, the hydroxypropyl methylcellulose has a viscosity of about 2 cps to about 8 cps, more preferably about 2 cps to about 6 cps, as described above.

In another embodiment, the pharmaceutical compositions of this example are:

About 23 mg to about 27 mg of finely divided eplerenone;

About 34 mg to about 38 mg of lactose;

About 14 mg to about 17 mg of microcrystalline cellulose; And

About 3 mg to about 6 mg of croscarmellose sodium; And

About 1 mg to about 4 mg of hydroxypropyl methylcellulose.

Such pharmaceutical compositions optionally comprise about 0.25 mg to about 1.5 mg of sodium lauryl sulfate; Talc of about 0.25 mg to about 1.5 mg; And about 0.1 mg to about 1 mg of magnesium stearate. Preferably, the hydroxypropyl methylcellulose has a viscosity of about 2 cps to about 6 cps, as described above.

In another embodiment, the pharmaceutical compositions of this example are:

About 48 mg to about 52 mg of finely divided eplerenone;

About 70 mg to about 73 mg of lactose;

About 29 mg to about 33 mg of microcrystalline cellulose; And

About 6 mg to about 10 mg of croscarmellose sodium; And

About 4 mg to about 6 mg of hydroxypropyl methylcellulose.

Such pharmaceutical compositions optionally comprise about 1 mg to about 2.5 mg of sodium lauryl sulfate; Talc of about 1 mg to about 2.5 mg; And about 0.5 mg to about 1.5 mg magnesium stearate. Preferably, the hydroxypropyl methylcellulose has a viscosity of about 2 cps to about 6 cps, as described above. The composition is preferably in the form of unit dose tablets.

In another embodiment, the pharmaceutical compositions of this example are:

About 98 mg to about 102 mg of finely divided eplerenone;

About 141 mg to about 145 mg of lactose;

About 60 mg to about 64 mg of microcrystalline cellulose; And

About 16 mg to about 18 mg of croscarmellose sodium; And

About 9 mg to about 11 mg of hydroxypropyl methylcellulose.

Such pharmaceutical compositions optionally comprise about 3 mg to about 4 mg of sodium lauryl sulfate; Talc of about 3 mg to about 4 mg; And about 1 mg to about 2 mg magnesium stearate. Preferably, the hydroxypropyl methylcellulose has a viscosity of about 2 cps to about 6 cps, as described above. The composition is preferably in the form of unit dose tablets.

In another embodiment, the pharmaceutical composition of this example comprises lactose, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl methylcellulose, sodium lauryl sulfate, talc and magnesium stearate.

In yet another embodiment, the pharmaceutical composition releases at least 50% of the eplerenone included in the composition in vitro in about 15 minutes in the SDS-containing medium. More preferably, about 50% of the finely divided eplerenone dissolves in about 20 minutes, about 80% dissolves in about 45 minutes, and at least 90% dissolves in about 90 minutes using a 0.1N HCl solution evaluation. Even more preferably, about 50% of the finely divided eplerenone is dissolved in about 15 minutes, about 80% is dissolved in about 30 minutes and at least about 90% is dissolved in about 45 minutes.

In yet another embodiment, the pharmaceutical composition can release in vitro at least about 50% of the eplerenone contained in the composition in about 15 minutes in an SDS-containing medium and is suitable for oral administration once or twice a day. Epulenone and one or more carrier materials finely divided into oral unit dosage forms. More specifically, about 50% of the finely divided eplerenone is dissolved in about 15 minutes, about 80% is dissolved in about 30 minutes and at least about 90% is dissolved in about 45 minutes. More specifically, such pharmaceutical compositions comprise Eppler and at least one carrier material selected from the group consisting of lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl methylcellulose, sodium lauryl sulfate, talc and magnesium stearate. Includes Lennon. It is particularly preferred that the various components of the composition be present in the following amounts or weight fractions.

In another embodiment, the pharmaceutical compositions of this example are:

About 15 mg to about 35 mg of finely divided eplerenone;

About 48 mg to about 68 mg of lactose;

About 2 mg to about 22 mg of microcrystalline cellulose; And

About 0.1 mg to about 10 mg of croscarmellose sodium.

Such pharmaceutical compositions optionally comprise about 0.1 to about 7 weight percent sodium lauryl sulfate; About 0.1 to about 10 weight percent talc; About 0.1 to about 10 weight percent magnesium stearate; And from about 0.1 to about 10 weight percent colloidal silicon dioxide. The composition is preferably in the form of a unit dose capsule.

Even more preferably, the pharmaceutical composition of this example is:

About 20 to about 30 weight percent of finely divided eplerenone;

About 53 to about 63 weight percent of lactose;

About 6.5 to about 16.5 weight percent microcrystalline cellulose; And

About 0.5 to about 6 weight percent of croscarmellose sodium.

Such pharmaceutical compositions optionally comprise about 0.25 to about 4 weight percent sodium lauryl sulfate; About 0.5 to about 5 weight percent talc; And from about 0.25 to about 5 weight percent magnesium stearate; And from about 0.1 to about 5 weight percent colloidal silicon dioxide.

Even more preferably, the pharmaceutical composition of this example is:

About 23 to about 27 weight percent of finely divided eplerenone;

About 56 to about 60 weight percent of lactose;

About 9.5 to about 13.5 weight percent microcrystalline cellulose; And

From about 0.5 to about 3.5 weight percent croscarmellose sodium.

Such pharmaceutical compositions optionally comprise about 0.25 to about 1.5 weight percent sodium lauryl sulfate; About 1 to about 4 weight percent talc; And about 0.1 to about 1 weight percent magnesium stearate; And from about 0.1 to about 1.5 weight percent colloidal silicon dioxide.

Even more preferably, the pharmaceutical composition of this example is:

About 25.0% finely divided eplerenone;

About 57.9% by weight of lactose;

About 11.3% microcrystalline cellulose;

About 2% by weight of croscarmellose sodium;

About 0.5% sodium lauryl sulfate;

About 2.5% talc;

About 0.3% magnesium stearate; And

In the form of a capsule comprising about 0.5% colloidal silicon dioxide.

In another embodiment, the pharmaceutical compositions of this example are:

About 20 mg to about 110 mg of finely divided eplerenone;

About 48 mg to about 242 mg of lactose; And

About 2 mg to about 56 mg of microcrystalline cellulose.

Such pharmaceutical compositions optionally comprise about 0.25 mg to about 18 mg of croscarmellose sodium; About 0.1 mg to about 5 mg sodium lauryl sulfate; About 0.5 mg to about 8 mg of talc; About 0.1 mg to about 5 mg magnesium stearate; And from about 0.1 mg to about 5 mg of colloidal silicon dioxide.

In another embodiment, the pharmaceutical compositions of this example are:

About 23 to about 27 mg of finely divided eplerenone;

About 56 mg to about 60 mg of lactose;

About 9.5 mg to about 13.5 mg microcrystalline cellulose; And

About 0.5 mg to about 3.5 mg of croscarmellose sodium.

Such pharmaceutical compositions optionally comprise about 0.1 mg to about 1.5 mg of sodium lauryl sulfate; Talc of about 0.25 mg to about 4.5 mg; About 0.1 mg to about 1.5 mg magnesium stearate; And from about 0.1 to about 2.5 weight percent colloidal silicon dioxide.

In another embodiment, the pharmaceutical compositions of this example are:

About 48 mg to about 52 mg of finely divided eplerenone;

About 114 mg to about 118 mg of lactose;

About 21 mg to about 25 mg of microcrystalline cellulose; And

About 2 mg to about 6 mg of croscarmellose sodium.

Such pharmaceutical compositions optionally comprise about 1 mg to about 2.5 mg of sodium lauryl sulfate; About 2 mg to about 8 mg of talc; About 0.25 mg to about 1.5 mg magnesium stearate; And from about 0.1 to about 3 weight percent colloidal silicon dioxide. The composition is preferably in the form of unit dose capsules.

In another embodiment, the pharmaceutical compositions of this example are:

About 98 mg to about 102 mg of finely divided eplerenone;

About 229 mg to about 234 mg of lactose;

About 43 mg to about 48 mg of microcrystalline cellulose; And

About 6 mg to about 10 mg of croscarmellose sodium.

Such pharmaceutical compositions optionally comprise about 0.5 mg to about 4 mg of sodium lauryl sulfate; About 8 mg to about 12 mg of talc; About 0.5 mg to about 3 mg magnesium stearate; And from about 0.5 mg to about 4 mg of colloidal silicon dioxide. The composition is preferably in the form of unit dose capsules.

Modified Release Oral Formulations

Oral delivery of a pharmaceutical composition of the present invention may include a controlled release formulation comprising a controlled release formulation known in the art to provide prolonged or sustained delivery of the drug to the gastrointestinal tract by any number of mechanisms. Can be. Such extended or sustained release mechanisms include pH sensitive release from a dosage form based on changing pH of the small intestine; Slow corrosion of tablets or capsules; Secretion of secretion in the stomach based on the physical properties of the preparation; Bioadhesion in the form of a dose into the mucosa into the stomach; Or release by the enzyme of the eplerenone from the dosage form, and the like. The intended effect is to extend the entire period of time during which the eplerenone is delivered to the point of action by manipulation of the dosage form. Thus, enteric-coated and enteric-coated controlled release formulations are within the scope of the present invention.

The adjusted release composition is in the range as described above, ie, from about 10 mg to about 1000 mg, more preferably from about 20 mg to 400 mg, even more preferably from about 25 mg to 200 mg, and even more preferably Comprises the desired amount of finely divided eplerenone in an amount of about 25 mg to 150 mg. Preferred adjusted release compositions are in the form of tablets or capsules, in particular tablets or capsules comprising finely divided eplerenone in an amount of 25 mg, 50 mg, 100 mg or 150 mg. The adjusted release composition may or may not be in single dose form. Such controlled release compositions, however, are preferably in unit dose oral form. Release tablets or capsules adjusted once a day generally comprise eplerenone in the range of about 25 mg to about 150 mg.

The adjusted-release dose, as defined in US Pharmacopoeia XI, exhibits at least a twofold reduction in the frequency of dosing compared to drugs present in deferred release dose forms and conventional dose forms that release the drug immediately after administration. Extended release dosage forms that are acceptable. The adjusted release composition may be in the form of sustained release or delayed / modified release and is preferred.

One form of controlled release composition achieves controlled release, for example, by the use of a substrate tablet composition. Suitable substrates that form the material include waxes (eg, carnauba, beeswax, paraffin wax, ceresin, shellac wax, fatty acids, and fatty alcohols); Oils, cured oils or fats (eg, cured rapeseed oil, taste oil, tallow, palm oil, and soybean oil); Polymers (eg, hydroxypropyl cellulose, polyvinypyrrolidone, hydroxypropyl methyl cellulose, polyethylene glycol, methacrylate (PMMA), and carbomer); Alginate; Xantham gum; And other carrier materials commonly known in the art. Other suitable substrates for purifying the material include microcrystalline cellulose, powdered cellulose, ethyl cellulose and the like. Other types of controlled release compositions can obtain controlled release by the use of granules, coated powders, pills, and the like, by multi-layering, and / or by suitable coatings. Another adjusted release composition comprises a vibration pump (as described in GB 2207052, published January 25, 1989), or a combination thereof.

Suitable coating materials for use in the preparation of the adjusted release composition include polymethacrylates, polyethylene glycols, hydroxypropyl, including ethyl cellulose, cellulose acetate butyrate, cellulose acetate, quaternary ammonium groups or other pharmaceutically acceptable polymers. All pharmaceutically acceptable polymers such as cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, and polyvinyl alcohol; Monomeric substances such as sugars, including lactose, sucrose, fructose and mannitol; Salts including sodium chloride, potassium chloride and derivatives; Organic acids including fumaric acid, succinic acid, lactic acid and tartaric acid and mixtures thereof; Polyvinyl acetate phthalate, cellulose acetate phthalate, cellulose acetate primerate, shellac, enteric polymers including zein, and polymethacrylates containing carboxyl groups. Such polymers may be applied as solutions or latexes. Other barriers can be used such as waxes.

The coating composition may be plasticized depending on the nature of the coating mixture, such as the main component or mixture of components or the glass transition temperature of the solvent used to apply the coating composition. Suitable plasticizers may be added at about 0% to about 50% of the weight of the coating composition. Such plasticizers include, for example, diethyl phthalate, citrate esters, polyethylene glycols, glycerol, acetylated glycerides, and castor oil.

Tablets or capsules comprising finely divided eplerenone may be coated to produce a controlled release dose directly, or may comprise a plurality of coated cores containing eplelenone. As used herein, "center" refers to one element of a composition comprising eplelenone and various carriers. Each central portion may comprise an amount of finely divided eplerenone in the range of about 0.1% to 95%, preferably about 10% to 80% by weight based on the total weight of the central portion. The central portion may generally be about 200 μm to 1700 μm in diameter. The pill is the central part coated with a coating which consists of all suitable coatings.

Such controlled release compositions can be prepared by prilling, spray drying, pan coating, contact coating, top spray, tablets, coacervation and the like. The particle size of the adjusted release component other than the finely divided eplerenone in the dosage form depends on the technique used. Particle size is 500 μm or less in microns for powder technology (mixtures, spray drying, dispersion, etc.); 5 μm to 1700 μm for coating techniques (warster, top spray, bottom spray, spray drying, molding, layering, etc.); And 1 mm to 20 mm for purification techniques. The controlled release form of the finely divided eplerenones is then combined in a single dose such that the amount of eplerenone in the composition of the present invention provides the desired dose. For example, standard coating procedures as described in Remington's Pharmaceutical Sciences, 18th (1990) may be conveniently used.

The composition may comprise finely divided eplerenone in immediate release form in combination with finely divided eplerenone in controlled release form. The immediate release form of such a composition may include an amount of finely divided eplerenone that is from about 0.5% to about 90% of the total amount of eplerenone in the composition, in a controlled release form that includes the remainder of the finely divided eplerenone. As a result, the final composition supplies the amount of finely divided eplerenone for immediate release and the amount of additional finely divided eplerenone for controlled release.

The following non-limiting examples illustrate the use of the components listed above to produce the compositions according to the invention.

When the composition of the present invention is in the form of a pill product, the pill may be present in sachets, capsules or tablets. The following non-limiting examples illustrate the pills in the capsule (particle size 200 μm to 1700 μm). All quoted ranges are% w / w.

Many of these elements, including finely divided epilelenones, or the core, may be used to layer the eplerenone (or mixture of eplelenone and other carrier materials) on an inert carrier by ejection / speronization, or by various processes. Are manufactured. The core itself may be an immediate release or a controlled release depending on the material and the method of preparation. The central portion may contain finely divided drugs of the required efficacy depending on the particular eplerenone dose, the required size, the required representation, and the subsequent process (coating, etc.). The central portion may comprise finely divided eplerenone in the range of about 0.1% to about 100% depending on the required dose, efficacy, method of preparation, and other properties.

The protruding centers are generally diluents / disintegrants such as finely divided eplerenones and, for example, microcrystalline cellulose (range from about 0.5% to about 99.9%), hydroxypropyl cellulose (about 0.5% to about 50% Binders); Fillers such as lactose (about 0.5% to about 90%); And other carrier materials. The protruding center may contain only drugs and binders, if desired.

Protruding cores with controlled release properties are generally swollen / gelled polymers, such as finely divided eplelenone and hydroxypropyl cellulose (range from about 0.5% to about 50%), or acetyl alcohol (about 10% to about 90). Anaerobic substances). The layered core may comprise inert carriers such as finely divided eplerenones and sugar balls (about 10% to about 90%) with a binder (about 0.1% to about 50%). The central portion may include diluents, wetting agents and other additives. The binder may be immediate release (hydroxypropyl cellulose, hydroxypropyl methylcellulose, etc.), adjusted release (ethyl cellulose, cellulose acetate butyrate, etc.), or delayed / modified release (eg, hydroxypropyl methylcellulose phthalate, Enteric binders such as polyvinylacetate phthalate).

The portion of the final dosage form may be an immediate release center made by the above process. Optionally, the immediate release center can be coated with a shell that disintegrates or dissolves quickly for aesthetic, handling, or stability purposes. Suitable materials include polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, and polymethacrylates comprising free amino groups. Such materials may include plasticizers, semi-viscous agents, and / or diluents. An addition of about 3% of the core weight as the coating material is generally considered to provide a continuous shell over this size range.

The adjusted release portion of the center may be provided by the adjusted release center, the adjusted release center further modified by the overcoat, or the immediate release center modified by the overcoat as described above.

Typical coating compositions for making controlled release components may include from about 15% to about 85% of the insoluble substrate polymer by weight of the coating composition, and from about 15% to about 85% of the water-soluble material by weight of the coating composition. Optionally, from about 0.1% to about 100% of the enteric polymer may be used or included in the weight of the coating composition. Suitable insoluble matrix polymers include ethyl cellulose, cellulose acetate butyrate, cellulose acetate, and polymethacrylates including four ammonium groups or other pharmaceutically acceptable polymers. Suitable water soluble materials include polymers such as polyethylene glycol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol; Monomeric materials such as sugar (eg, lactose, sucrose, fructose, mannitol, etc.); Salts (eg, sodium chloride, potassium chloride, etc.); Organic acids (eg, fumaric acid, succinic acid, lactic acid, tartaric acid, etc.); And mixtures thereof. Suitable enteric polymers include polyhydroxy including hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, shellac, zein, carboxyl groups. Methacrylate and the like.

The coating composition is plasticized depending on the nature of the coating mixture, such as the glass transition temperature of the solvent or the main component or mixture of components used to be applied to the coating composition. Suitable plasticizers may be added at about 0.1% to about 50% by weight of the coating composition. Such plasticizers can be selected, for example, from diethyl phthalate, citrate esters, polyethylene glycols, glycerol, acetylated glycerides, acetylated citrate esters, dibutyl sebacate, castor oil and the like.

The coating composition may comprise a filler. Fillers may comprise from about 0.1% to about 100% by weight based on the total weight of the coating composition. Fillers may be insoluble materials such as silicon dioxide, titanium dioxide, talc, kaolin, alumina, starch, pulverized cellulose, microcrystalline cellulose, potassium chlorlin, and the like.

The coating composition may be applied as a latex or solvent in an aqueous solvent of an organic solvent or a mixture thereof. If a solution is applied, the solvent is present in an amount from about 25% to about 99%, preferably from about 85% to about 97% of the weight based on the total weight of the dissolved solid. Suitable solvents are water, low cost alcohols, low cost hydrocarbons, ketones or mixtures thereof. When a latex is applied, the solvent is from about 25% to about 97% by weight based on the amount of polymeric material in the latex, preferably about Present from 60% to about 97%.

Suitable tablet formulations may include finely divided eplerenones with puffed / gelled polymers such as L-hydrogipropyl cellulose mixed with filler such as microcrystalline cellulose. Tablet carriers may be processed together (ie, spray dried) prior to compression. Substrate tablets of this type often exhibit rapid initial release until the polymer swells and gels, which leads to controlled release for the remainder of the drug.

The amount of immediate release and the course of controlled release can be altered by changing the nature of the carrier material used. If there are sufficient immediate release components, the amount of finely divided eplerenone may be included to rapidly dissolve the outer shell of the mesomeric body such as polyethylene glycol or hydroxypropyl methylcellulose.

Typical substrate tablets may include from about 5% to about 70% of the swollen / gelled polymer based on the total weight of the tablet, and from about 15% to about 90% of the diluent based on the total weight of the tablet. Additional diluents may be included from about 0.1% to about 65% by weight based on the total weight of the tablet. It may be a soluble substance such as lactose, mannitol, sorbitol, or the like, or an insoluble substance such as tribasic calcium phosphate powdered cellulose or all of various (corn, wheat, potatoes, etc.).

In addition, the tablet may include from about 0.1% to about 8% of a lubricant by weight based on the total weight of the tablet. Glidants can be selected from metal stearates, stearic acid, hydrated oils, soybean or castor oil, sodium stearyl perate, polytetrafluoroethylene, talc and the like.

Tablets may be coated for aesthetic, handling, or stability purposes, or to increase the amount of release portion of the eplerenone immediately. In this latter case, the finely divided eplerenone is dissolved or suspended in the coating solution and sprayed onto the tablet until the desired amount of eplelenone is added. Suitable coating materials include polyethylene glycol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, sugar, wax, or a mixture of these.

Coating materials may be added to any desired thickness but weight gains of about 1% to about 20% are common, about 2% to about 10% are preferred, and about 2% to about 5% are more preferred. The plasticizer may be present from about 0.1% to about 50% by weight based on the total weight of the identity of the coating material. Examples of plasticizers include diethyl phthalate, citrate esters, acetylated citrate esters, polyethylene glycols, glycerol, dibutyl sebacate, acetylated monoglycerides, castor oil and the like.

The coating composition may include semi-viscous agents such as talc, kaolin, titanium dioxide, silicon dioxide, alumina, starch, polyacrylic potassium, microcrystalline cellulose and the like.

The coating material may be applied to eplelenone particles, processed eplelenone particles (ie, core, granules), finished tablets, or finished capsules.

The coating composition may also include a filler. Fillers may comprise from about 0.1% to about 100% by weight based on the total weight of the coating composition and include silicon dioxide, titanium dioxide, talc, kaolin, alumina, starch, pulverized cellulose, microcrystalline cellulose, polyacrylic potassium It may be an insoluble material such as. The coating composition may include other ingredients such as dyes and waxes.

The shells can be applied in solution or suspension from aqueous and organic solvents using solution concentrations and apparatus familiar to those skilled in the art. The coating composition may be applied as a solution or latex in an organic or water soluble solvent or mixture thereof. If a solution is applied, the solvent is present from about 25% to about 99%, preferably from about 85% to about 97% by weight based on the total weight of the dissolved solids. Suitable solvents are water, low cost alcohols such as ethanol and iso-propanol, low cost hydrogen chlorides such as chloroform and dichloromethane, ketones such as acetone and methyl ethyl ketone, or mixtures thereof. If latex is applied, the solvent is present from about 25% to about 97%, preferably from about 60% to about 97% by weight based on the amount of polymeric material in the latex. The solvent may be water by far.

Optionally, the controlled release component of the tablet can be supplied in the form of a controlled release pill, and the immediate release component can be included in the body of the tablet. Such tablets disintegrate to release the immediate release drug and the adjusted release pill. Pills may be present from about 1% to about 60%, preferably from about 5% to about 50%, and more preferably from about 5% to about 40% by weight of the tablet. Suitable substrate materials for this type of purification are microcrystalline cellulose, starch and the like.

Immediate release forms of microcrystalline eplerenone may be present in fast dissolving dosage forms. The immediate release form may be in solid form or in the form of active molecular dispersion in the polymer matrix. The polymer substrate can be selected from biologically acceptable polymers such as, for example, cellulose ethers such as ethyl cellulose, or cellulose esters such as, for example, cellulose acetate butyrate. The immediate release form may be a simple particle of eplerenone lying on the core containing the eplelenone.

The composition of the present invention, when in tablet or such form, may comprise two forms of finely divided eplerenone, for example as discrete components in a multi-layer tablet, wherein one or more layers are in a controlled release form. Includes finely divided eplerenones. Optionally, the composition of the present invention may be in tablet form, wherein the immediate release form is present in the shell and the adjusted release form constitutes the central portion. Optionally, two forms of finely divided eplerenone may be dispersed through purification.

The compositions of the present invention can be produced by providing a central portion comprising finely divided eplerenone adjusted release components coated with an enteric or delayed release coating. The central portion may be in the form of beads compressed into tablets. The coated core may be compressed into tablets according to a powder mixture comprising additional eplelenones or packed in combination with the eplelenones coated in the capsule shell. As a result, the final composition supplies the amount of efluenene for immediate release and the additional amount of eplerenone for controlled release immediately after administration.

The controlled release form of finely divided eplerenone is equivalent to supplying sustained release of eplerenone. Preferably, the adjusted or sustained release form provides a therapeutic effect throughout the cycle of at least about 12 hours, with a sustained therapeutic effect cycle of 12 to 24 hours, particularly preferred.

The controlled release form may be in the form of coated beads or granules of finely divided eplerenone. Coated finely divided eplerenone may be combined with uncoated or weakly coated finely divided eplerenone to provide the controlled release composition of the present invention. As used herein, the term "weakly coated" means a coating that disintegrates rapidly for aesthetic, handling or stability purposes. It can then be filled into capsules or formed into tablets. Microencapsulation can also be used to produce a controlled release form of finely divided eplerenones.

The coating or substrate material can be any suitable material. The coating or substrate material may be a polymer or a wax. Waxes include natural oils and fats and hardened oils such as hardened rapeseed oil, hardened castor oil, hardened tallow, palm oil and the like; And any suitable wax or wax such as carnauba wax, beeswax, paraffin wax, ceresin wax, shellac wax or wax such as fatty acid.

Additional adjusted release formulations are described, for example, in US Pat. No. 5,190,765 to Zhao et al .; US Patent No. 5,160,744 to Zhao et al .; U.S. Patent No. 5,082,668 to Cheng et al .; U.S. Patent No. 4,847,093 to Ayer et al .; December 8, 1993, published EP 572942 A2; September 28, 1988, published EP 284039 A2; September 28, 1988, published EP 284039 A2; September 23, 1987, published EP 238189 A1; December 8, 1994, published WO 94/27582; August 20, 1992, published WO 92/13547; And January 23, 1992, by suitable variations of the formulations and methods disclosed in WO92 / 00729.

In one embodiment of the present invention, the pharmaceutical composition is in a controlled release oral dosage form, preferably tablets or capsules, wherein the release of the eplerenones comprises the finely divided proportions of the eplerenones over a period of several hours. Adjusted by the use of releasing hydrophilic substrates. Such hydrophilic substrates can be prepared, for example, by combining hydroxypropyl methylcellulose with an agent combined with other carrier materials. The required amount of hydroxypropyl methylcellulose depends on the desired release rate. Exemplary compositions having various dissolution rates in vivo are described in the Examples below.

In a typical formulation, hydroxypropyl methylcellulose is combined with finely divided eplerenone and other carrier materials, followed by high shear wet granulation, fluid bed drying, mixing and compression into tablet dosage form. When hydroxypropyl methylcellulose is combined with a hydrophilic substrate to provide a controlled release dosage form, the hydroxypropyl methylcellulose used is a high molecular weight (or high viscosity) hydroxypropyl methylcellulose. The term “high molecular weight (or high viscosity) hydroxypropyl methylcellulose” refers to 2% viscosity (ie, viscosity of 2% solution of hydroxypropyl methylcellulose in 20 ° C. water) in the range of about 3,500 cps to about 5,600 cps. Hydroxypropyl methyl cellulose having.

When the tablet is exposed to an aqueous medium, such as gastrointestinal tract, the tablet surface is wet and the polymer begins to partially hydrate while forming an outer gel layer. This outer gel layer completely hydrates and begins to corrode into the aqueous fluid. Water continues to osmise towards the center of the tablet allowing the other gel layer to form below the dissolving outer gel layer. This continuous osmotic gel layer maintains a uniform release of eplelenone by diffusion from the gel layer and exposure through tablet corrosion.

In general, increasing concentrations of polymer in the substrate cause the gel formed on the tablet surface to increase viscosity and cause diffusion and decrease in release of eplerenone. A typical two hour adjusted release formulation (i.e., a formulation that releases about 50% of influenon in vitro for a two hour cycle after ingestion) is about 2% to about 20%, preferably about 3% to about 17%, and More preferably about 4% to about 14%, by weight of the composition, high molecular weight hydroxypropyl methylcellulose. A typical four hour adjusted release formulation (i.e., one that releases about 50% of the influenon in vitro during the time period after ingestion) is from about 5% to about 45%, preferably from about 7% to about 35%, and More preferably about 8% to about 28% by weight of the composition, high molecular weight hydroxypropyl methylcellulose. A typical 6 hour adjusted release formulation (ie, a formulation that releases about 505 of in vitro eplanenone during the 6 hour cycle after ingestion) is about 10% to about 45%, preferably about 12% to about 35%, and More preferably 14% to about 35%, high molecular weight hydroxypropyl methylcellulose by weight of the composition.

Changing the tablet size and shape affects the volume ratio of the tablet and thus the drug releases kinetics from the hydrophobic substrate of the tablet. In general, the release of finely divided eplerenone from the pharmaceutical composition of the present invention is enhanced when the tablet size is reduced and / or the tablet shape changes from circular to caplet. The particle size of the polymer has been found to affect the rate at which finely divided eplerenone is released from the tablet. As the polymer particle size decreases, the hydration of the polymer is believed to result in slower drug release and occur faster on the tablet surface. In addition, since tablet coatings can alter the eplerenone release kinetics, the effect of the coating on drug release should be considered for coated tablets. The controlled release tablet test of the present invention indicates that the release of eplerenone from the tablet is substantially independent of the tablet compression force for a compression force between about 10 kN and about 40 kN.

In another embodiment, the pharmaceutical composition is:

About 24 to about 35 weight percent of finely divided eplerenone;

About 25 to about 45 weight percent lactose monohydrate;

About 10 to about 25 weight percent microcrystalline cellulose; And

About 5 to about 50 weight percent hydroxypropyl methylcellulose.

Such pharmaceutical compositions optionally comprise about 0.1 to about 2 weight percent talc; And / or about 0.25 to about 0.75 weight percent magnesium stearate.

More preferably, the pharmaceutical compositions of this example comprise about 25 to about 35 weight percent of finely divided eplerenone; About 35 to about 45 weight percent lactose; About 14.5 to about 24.5 weight percent of microcrystalline cellulose; About 1 to about 11 weight percent high molecular weight hydroxypropyl methylcellulose; And from about 0.5 to about 8 weight percent low molecular weight hydroxypropyl methylcellulose. Such pharmaceutical compositions optionally comprise about 0.1 to about 6 weight percent of talc; And about 0.1 to about 5.5 weight percent magnesium stearate.

In one embodiment, the pharmaceutical composition is

About 20 to about 40 weight percent of finely divided eplerenone;

About 30 to about 50 weight percent of lactose;

About 9.5 to about 29.5 weight percent of microcrystalline cellulose;

About 1 to about 16 weight percent high molecular weight hydroxypropyl methylcellulose; And

Controlled release composition comprising from about 0.5 to about 13 weight percent low molecular weight hydroxypropyl methylcellulose.

Such pharmaceutical compositions optionally comprise about 0.1 to about 10 weight percent talc; And about 0.1 to about 10 weight percent magnesium stearate. Preferably, the low molecular weight hydroxypropyl methylcellulose has a viscosity of about 2 cps to about 8 cps, more preferably about 2 cps to about 6 cps as described above. Preferably, the high molecular weight hydroxypropyl methylcellulose has a 2% viscosity value of about 3500 cps to about 5600 cps as described above. The composition is preferably in the form of unit dosage tablets.

More preferably, the pharmaceutical compositions of this example comprise about 25 to about 35 weight percent of finely divided eplerenone; About 35 to about 45 weight percent lactose; About 14.5 to about 24.5 weight percent of microcrystalline cellulose; About 1 to about 11 weight percent high molecular weight hydroxypropyl methylcellulose; And from about 0.5 to about 8 weight percent low molecular weight hydroxypropyl methylcellulose. Such pharmaceutical compositions optionally comprise about 0.1 to about 6 weight percent of talc; And about 0.1 to about 5.5 weight percent magnesium stearate.

Even more preferably, the pharmaceutical compositions of this example comprise about 28 to about 32 weight percent of finely divided eplerenone; About 38 to about 42 weight percent lactose; About 17.5 to about 21.5 weight percent of microcrystalline cellulose; About 4 to about 8 weight percent of high molecular weight hydroxypropyl methylcellulose; And about 2 to about 5 weight percent low molecular weight hydroxypropyl methylcellulose. Such pharmaceutical compositions optionally comprise about 0.1 to about 3 weight percent talc; And about 0.1 to about 2.5 weight percent magnesium stearate.

In another embodiment, the pharmaceutical composition is

About 20 to about 40 weight percent of finely divided eplerenone;

About 15 to about 47 weight percent lactose;

About 3.5 to about 28.5 weight percent of microcrystalline cellulose;

About 1 to about 45 weight percent of high molecular weight hydroxypropyl methylcellulose; And

Controlled release composition comprising from about 0.5 to about 13 weight percent low molecular weight hydroxypropyl methylcellulose.

Such pharmaceutical compositions optionally comprise about 0.1 to about 10 weight percent talc; And about 0.1 to about 10 weight percent magnesium stearate. Preferably, the low molecular weight hydroxypropyl methylcellulose has a viscosity of about 2 cps to about 8 cps, more preferably about 2 cps to about 6 cps as described above, while the high molecular weight hydroxypropyl methyl cellulose has a viscosity of about 3500 cps to about 5 600 cps. Has a 2% viscosity value. The composition is preferably in the form of unit dose tablets.

More preferably, the pharmaceutical compositions of this example comprise about 25 to about 35 weight percent of finely divided eplerenone; About 22 to about 42 weight percent lactose; About 8.5 to about 23.5 weight percent of microcrystalline cellulose; About 5 to about 35 weight percent of high molecular weight hydroxypropyl methylcellulose; And from about 0.5 to about 8 weight percent low molecular weight hydroxypropyl methylcellulose. Such pharmaceutical compositions optionally comprise about 0.1 to about 6 weight percent of talc; Dimming may additionally comprise about 0.1 to about 5.5 weight percent magnesium stearate.

Even more preferably, the pharmaceutical compositions of this example comprise about 28 to about 32 weight percent of finely divided eplerenone; About 25 to about 39 weight percent of lactose; About 11.5 to about 20.5 weight percent of microcrystalline cellulose; About 10 to about 35 weight percent of high molecular weight hydroxypropyl methylcellulose; And about 2 to 5 weight percent low molecular weight hydroxypropyl methylcellulose. Such pharmaceutical compositions optionally comprise about 0.1 to about 3 weight percent talc; And about 0.1 to about 2.5 weight percent magnesium stearate.

In another embodiment, the pharmaceutical composition is

About 20 to about 40 weight percent of finely divided eplerenone;

About 20.5 to about 40.5 weight percent of lactose;

About 5 to about 25 weight percent microcrystalline cellulose;

About 10 to about 30 weight percent of high molecular weight hydroxypropyl methylcellulose; And

Controlled release composition comprising from about 0.5 to about 13 weight percent low molecular weight hydroxypropyl methylcellulose.

Such pharmaceutical compositions optionally comprise about 0.1 to about 10 weight percent talc; And about 0.1 to about 10 weight percent magnesium stearate. Preferably, the low molecular weight hydroxypropyl methylcellulose has a viscosity of about 2 cps to about 8 cps, more preferably about 2 cps to about 6 cps as described above, while the high molecular weight hydroxypropyl methyl cellulose is about 3500 cps as described above. And a 2% viscosity value of from about 5600 cps. The composition is preferably in the form of unit dosage tablets.

Even more preferably, the pharmaceutical compositions of this example comprise about 28 to about 32 weight percent of finely divided eplerenone; About 28.5 to about 32.5 weight percent lactose; About 13 to about 17 weight percent microcrystalline cellulose; About 18 to about 22 weight percent of high molecular weight hydroxypropyl methylcellulose; And about 2 to about 5 weight percent low molecular weight hydroxypropyl methylcellulose. Such pharmaceutical compositions optionally comprise about 0.1 to about 3 weight percent talc; And about 0.1 to about 2.5 weight percent magnesium stearate.

In another embodiment, the pharmaceutical composition of this embodiment is

About 25 to about 150 mg of finely divided eplerenone;

About 12.5 to about 190 mg of lactose;

About 2 to about 100 mg of microcrystalline cellulose;

About 10 to about 80 mg of high molecular weight hydroxypropyl methylcellulose; And

About 1 to about 25 mg of low molecular weight hydroxypropyl methylcellulose.

Such pharmaceutical compositions optionally comprise about 0.5 to about 15 mg of talc; And about 0.1 to about 10 mg of magnesium stearate. Preferably, the low molecular weight hydroxypropyl methylcellulose has a viscosity of about 2 cps to about 8 cps, more preferably about 2 cps to about 6 cps as described above, while the high molecular weight hydroxypropyl methyl cellulose has a viscosity of about 3500 cps to about 5 600 cps. Has a 2% viscosity value.

In another embodiment, the pharmaceutical composition of this embodiment is

About 95 to about 105 mg of finely divided eplerenone;

About 128 to about 139 mg of lactose;

About 60 to about 70 mg of microcrystalline cellulose;

About 10 to about 25 mg of high molecular weight hydroxypropyl methylcellulose; And

About 5 to about 15 mg of low molecular weight hydroxypropyl methylcellulose.

Such pharmaceutical compositions optionally comprise about 0.5 to about 8 mg of talc; And about 0.1 to about 7 mg magnesium stearate. The composition is preferably in the form of unit dose tablets.

More preferably, the pharmaceutical compositions of this example comprise about 98 mg to about 102 mg of finely divided eplereno; About 131 mg to about 136 mg of lactose; About 63 mg to about 67 mg of microcrystalline cellulose; About 18 mg to about 22 mg of high molecular weight hydroxypropyl methylcellulose; And about 8 mg to 12 mg of low molecular weight hydroxypropyl methylcellulose. Such pharmaceutical compositions optionally comprise about 2 mg to about 5 mg of talc; And about 0.5 to about 3 weight percent magnesium stearate.

In another embodiment, the pharmaceutical composition of this embodiment is

About 45 to about 55 mg of finely divided eplerenone;

About 35 to about 55 mg of lactose;

About 17.5 to about 27.5 mg of microcrystalline cellulose;

About 37 to about 47 mg of high molecular weight hydroxypropyl methylcellulose; And

About 1 to about 10 mg of low molecular weight hydroxypropyl methylcellulose.

Such pharmaceutical compositions optionally comprise about 0.5 to about 7 mg of talc; And about 0.1 to about 6 mg magnesium stearate. The composition is preferably in the form of unit dose tablets.

More preferably, the pharmaceutical compositions of this example comprise about 48 mg to about 52 mg of finely divided eplerenone; About 43 mg to about 47 mg of lactose; About 20.5 mg to about 24.5 mg of microcrystalline cellulose; About 40 mg to about 44 mg of high molecular weight hydroxypropyl methylcellulose; And about 3 mg to 7 mg of low molecular weight hydroxypropyl methylcellulose. Such pharmaceutical compositions may optionally contain about 0.5 mg to about 3 mg of talc; And about 0.1 to about 3 weight percent magnesium stearate.

In another embodiment, the pharmaceutical composition of this embodiment is

About 95 to about 105 mg of finely divided eplerenone;

About 110 to about 195 mg of lactose;

About 50 to about 70 mg of microcrystalline cellulose;

About 30 to about 50 mg of high molecular weight hydroxypropyl methylcellulose; And

About 5 to about 15 mg of low molecular weight hydroxypropyl methylcellulose.

Such pharmaceutical compositions optionally comprise about 0.5 to about 8 mg of talc; And about 0.1 to about 7 mg magnesium stearate. The composition is preferably in the form of unit dose tablets.

More preferably, the pharmaceutical compositions of this example comprise about 98 mg to about 102 mg of finely divided eplerenone; About 118 mg to about 122 mg of lactose; About 58 mg to about 62 mg of microcrystalline cellulose; About 38 mg to about 42 mg of high molecular weight hydroxypropyl methylcellulose; And about 8 mg to 12 mg of low molecular weight hydroxypropyl methylcellulose. Such pharmaceutical compositions optionally comprise about 2 mg to about 5 mg of talc; And about 0.5 to about 3 weight percent magnesium stearate.

In another embodiment, the pharmaceutical composition of this embodiment is

About 145 to about 155 mg of finely divided eplerenone;

About 175 to about 195 mg of lactose;

About 87.5 to about 97.5 mg of microcrystalline cellulose;

About 45 to about 55 mg of high molecular weight hydroxypropyl methylcellulose; And

About 10 to about 20 mg of low molecular weight hydroxypropyl methylcellulose.

Such pharmaceutical compositions optionally comprise about 0.5 to about 10 mg of talc; And about 0.1 to about 8 mg magnesium stearate. The composition is preferably in the form of unit dose tablets.

More preferably, the pharmaceutical compositions of this example comprise about 148 mg to about 152 mg of finely divided eplerenone; About 183 mg to about 187 mg of lactose; About 90.5 mg to about 94.5 mg microcrystalline cellulose; About 48 mg to about 52 mg of high molecular weight hydroxypropyl methylcellulose; And about 13 mg to 17 mg of low molecular weight hydroxypropyl methylcellulose. Such pharmaceutical compositions optionally comprise about 3 mg to about 7 mg of talc; And about 0.5 to about 4.5 weight percent magnesium stearate.

In another embodiment, the pharmaceutical composition of this embodiment is

About 95 to about 105 mg of finely divided eplerenone;

About 96.5 to about 106.5 mg of lactose;

About 45 to about 55 mg of microcrystalline cellulose;

About 61.5 to about 71.5 mg of high molecular weight hydroxypropyl methylcellulose; And

About 5 to about 15 mg of low molecular weight hydroxypropyl methylcellulose.

Such pharmaceutical compositions optionally comprise about 0.5 to about 8 mg of talc; And about 0.1 to about 7 mg magnesium stearate. The composition is preferably in the form of unit dose tablets.

More preferably, the pharmaceutical compositions of this example comprise about 98 mg to about 102 mg of finely divided eplerenone; About 99.5 mg to about 103.5 mg lactose; About 48 mg to about 52 mg of microcrystalline cellulose; About 64.5 mg to about 68.5 mg of high molecular weight hydroxypropyl methylcellulose; And about 8 mg to 12 mg of low molecular weight hydroxypropyl methylcellulose. Such pharmaceutical compositions optionally comprise about 2 mg to about 5 mg of talc; And about 0.5 to about 3 weight percent magnesium stearate.

In another embodiment, the pharmaceutical composition of this example comprises lactose, microcrystalline cellulose, hydroxypropyl methylcellulose, talc, and magnesium stearate.

In another embodiment, the pharmaceutical composition releases in vitro at least about 50% of the eplerenone included in the composition after at least about 1.5, preferably after at least about 1.75, even more preferably after about 2 hours.

In another embodiment, the pharmaceutical composition releases in vitro at least about 50% of the eplerenone included in the composition at least about 3.5 hours, preferably at least about 3.75 hours, and even more preferably about 4 hours. do.

In another embodiment, the pharmaceutical composition releases in vitro at least about 50% of the eplerenone included in the composition at least about 5.5 hours, preferably at least about 5.75 hours, and even more preferably about 6 hours. do.

In another embodiment, the pharmaceutical composition comprises finely divided eplerenone and one or more carrier materials, and is in an oral unit dosage form suitable for oral administration once or twice a day, and at least about 1.5 hours after ingestion of the composition At least about 50% of the eplerenone contained therein is released in vitro. Even more preferably, such pharmaceutical compositions comprise eplerenone and at least one carrier material selected from the group consisting of lactose monohydrate, microcrystalline cellulose, hydroxypropyl methylcellulose, talc, and magnesium stearate. It is particularly preferred that the various traces of the adjusted release substrate are present in the amounts or weight fractions described below.

Other active ingredients

The pharmaceutical compositions of the present invention are also useful for the administration of other 9,11-epoxy-20-spiroxane compounds, especially their 9,11-epoxy-20-spiroxane compounds, which are aldosterone antagonists. Such pharmaceutical compositions can be prepared as described herein by substituting eplerenone at a comparable weight fraction of the desired 9,11-epoxy-20-spiroxane. The 9,11-epoxy-20-spiroxane used in the manufacture of such pharmaceutical compositions can be prepared, for example, as described in US Pat. No. 4,559,332 to Grove et al. Such 9,11-epoxy-20-spiroxanes are compounds of

9α, 11α-epoxy-7α-methoxycarbonyl-15β, 16β-methylene-20-spirox-4-ene-3,21-dione;

9α, 11α-epoxy-7α-isopropoxycarbonyl-20-spirox-4-ene-3,21-dione;

9α, 11α-epoxy-7α-ethoxycarbonyl-20-spirox-4-ene-3,21-dione;

9α, 11α-epoxy-7α-6β, 7β-methylene-20-spirox-4-ene-3,21-dione;

9α, 11α-epoxy-7α-6β, 7β; 15β, 16β-bis-methylene-20-spirox-4-ene-3,21-dione;

9α, 11α-epoxy-17β-hydroxy-6β, 7β-methylene-3-oxo-17α-pregan-4-ene-21-carboxylic acid;

9α, 11α-epoxy-17β-hydroxy-6β, 7β-methylene-3-oxo-17α-pregan-4-ene-21-carboxylic acid methyl ester;

9α, 11α-epoxy-17β-hydroxy-6β, 7β; 15β, 16β-bis-methylene-3-oxo-17α-pregan-4-ene-21-carboxylic acid methyl ester;

9α, 11α-epoxy-6β, 7β-methylene-20-spiroxa-1,4-diene-3,21-dione;

9α, 11α-epoxy-17β-hydroxy-7α-methoxycarbonyl-3-oxo-17α-pregan-4-ene-21-carboxylic acid;

9α, 11α-epoxy-17β-hydroxy-3-oxo-17β-pregan-4-ene-7α, 21-dicarboxylic acid dimethyl ester;

9α, 11α-epoxy-17β-hydroxy-7α-isopropoxycarbonyl-3-oxo-17α-pregan-4-ene-21-carboxylic acid;

9α, 11α-epoxy-17β-hydroxy-7α-ethoxycarbonyl-3-oxo-17α-pregan-4-ene-21-carboxylic acid;

9α, 11α-epoxy-6α, 7α-methylene-20-spirox-4-ene-3,21-dione;

9α, 11α-epoxy-17β-hydroxy-3-oxo-17α-pregan-4-ene-7α, 21-dicarboxylic acid dimethyl ester; And

9α, 11α-epoxy-17β-hydroxy-15β, 16β-methylene-3-oxo-17α-pregan-4-ene-7α, 21-dicarboxylic acid dimethyl ester;

And pharmaceutically acceptable salts thereof.

Treatment method

The present invention also relates to a therapeutic method of treating a condition or disorder in which treatment with an aldosterone receptor blocker is indicated, the method comprising orally administering one or more pharmaceutical ingredients as described above to a patient in need thereof. Dosage regimens for preventing, alleviating, and ameliorating such conditions or disorders correspond to oral administration once or twice daily, and more preferably corresponding to oral unit doses of 25 mg, 50 mg, 100 mg, or 150 mg of the aforementioned eplerenone unit. It is preferred, but may be modified depending on various factors. These factors include the type, age, weight, sex, diet, and medical condition and severity of the patient. Therefore, the dosage regimens employed substantially vary widely and may therefore deviate from the following preferred dosage regimens.

Initial treatment of patients suffering from a condition or disorder for which treatment with an aldosterone receptor blocker is indicated may begin with the indicated doses. Treatment generally continues over a period of weeks or months or years until the condition or disorder is rectified or eliminated, if necessary. Patients treated with the compositions disclosed herein can be routinely monitored by any method known in the art to determine the effectiveness of the method of treatment. Ongoing analysis of such data allows modification of the treatment regimen during treatment so that the best effective amount of a compound of the present invention is administered at any point in time and the course of treatment can be well observed. In this way, the treatment regimen / dose schedule can be reasonably modified over the course of treatment so that the lowest amount of eplerenone that is satisfactory is administered and the administration continues only as long as necessary to successfully treat the condition or disorder.

The invention also includes the use of finely divided eplerenone and cellulosic carrier materials in the manufacture of a medicament for the treatment or prevention of an aldosterone-mediated condition or disorder.

Preparation of Formulation

The present invention also relates to a method for preparing a pharmaceutical composition comprising finely divided eplerenone. If tablets or capsules are desired, methods such as wet granulation, dry granulation or direct compression or encapsulation methods can be employed.

Wet granulation is a preferred method for preparing tablets from the pharmaceutical compositions of the present invention. In the wet granulation process, the finely divided eplerenone (and, if desired, all carrier materials) are initially ground or finely ground to the desired particle size using a conventional mill or mill. Such milling or milling techniques are known in the art as a method for identifying the resulting particle size and distribution.

As noted above, the reduction in the D ₉₀ eplerenone particle size (ie, at least 90% of the size of the eplelenone particles) in the composition is about 400 microns or less and 25 microns or more, more preferably about 150 microns or less, Even more preferably about 100 microns or less, and even more preferably 90 microns or less. Particularly preferred D ₉₀ particle sizes are from about 30 to about 110 microns, and more preferably from about 30 to about 50 microns. In another preferred embodiment, the particularly preferred D ₉₀ particle size is about 50 to about 150 microns, and more preferably about 75 to about 125 microns. Eplerenone finely divided into such sizes can substantially increase the bioavailability of the eplelenone.

The finely divided eplerenones used exemplarily herein typically have a D ₉₀ value of about 30 to about 110 microns. Typical particle distributions are provided below for some specific examples.

Particle size distribution is determined using the following procedure.

Device and Reagents:

1. ^TM VIBRI feeder and RODOS ^TM diffusion system is equipped with a dry powder form, model H0790 my core Patek ^TM HELOS System Laser Light Diffraction Particle Size device.

2. 200-500mm focal length lens.

3. Corn starch, NF (example reference standard; D ₉₀ = 32.54, D ₇₅ = 20.50, D ₅₀ = 15.15 and D ₁₀ = 7.44 microns).

4. Control of finely divided eplerenones (exemplarily; D ₉₀ = 22.10, D ₇₅ = 22.10, D ₇₅ = 13.35, D ₅₀ = 7.57 and D ₁₀ = 10.8 microns).

Dispersion points 5, 10, 50, 75, 90 and 95%

For data collection:

Analysis process:

1. Check and install the lens.

2. Using corn starch, NF (reference standard), verify the functionality of the device in accordance with the installed device procedures.

3. Guaranteed control sample treatment and particle size distribution of finely divided eplerenone in singlet similar to previous treatment.

4. Weigh approximately 500 mg of sample and determine 3x particle size diffusion.

5. Calculate the mean standard deviation and percentage of standard deviation at each diffusion point.

6. Record n at 5, 10, 50, 75, 90, and 95 ^th percentiles for mean particle size, standard deviation, and integer.

The ground or finely divided eplerenone is then mixed with one or more carrier materials, for example in a high shear mixer granulator, a mixer in a planetary interlock, a twin-shell blender or a sigma mixer. Typically, the drug is mixed with diluent (s), disintegrant (s), binder (s) and optionally humectant (s) at this stage even if all or part of one or more carrier materials may be added at a later stage.

For example, when microcrystalline cellulose is employed as a diluent, the addition of a portion of microcrystalline cellulose during this mixing step and the addition of the remaining part after the following drying step increases the strength of the tablets produced and / or the degree of wear It turned out to decrease. In this situation, it is preferred that about 40% to about 50% of the microcrystalline cellulose is added into the granules and about 50% to about 60% of the microcrystalline cellulose is added out of the granules. In addition, this step of the process preferably comprises the mixing of eplelenone, lactose, microcrystalline cellulose, hydroxypropyl methylcellulose and, optionally, sodium lauryl sulfate. It has been found that a short mixing time of about 3 minutes can provide a dry powder mixture with a sufficiently uniform distribution of eplerenones.

Water is then added to the dry powder mixture and the mixture is well mixed for an additional period of time. Water may be added to the mixture at one time, slowly over a period of time, or in several portions over a period of time. Water is preferably added slowly over a period of time, preferably at least about 3 minutes to about 5 minutes. An additional mixing cycle of at least about 1 to about 3 minutes is generally completed after the addition of water, and a uniform distribution of water in the mixture appears to be certain and a suitable wet granulated mixture is produced.

It is generally preferred that the wet granulated mixture comprises from about 25% to about 45% water by weight. Although higher or lower water contents may be acceptable for constant formulation, lower water contents generally reduce the effect of producing granules with the desired compressibility and flowability, while higher water contents are generally This will increase the size of the granules.

 The wet granulated mixture is then dried, for example, in an oven or fluidized bed layer, preferably in a fluidized bed dryer. If desired, the wet granulated mixture may be wet milled, molded or spherical before drying, even if wet milling is desired. For the drying process, conditions such as inlet air temperature and drying time are adjusted to obtain the desired moisture content for the dried mixture. Increasing the water content from about 2% to about 4% is observed to decrease the initial tablet strength.

To the extent necessary, the dry granules are then reduced in size at the manufacturing stage for compression. Conventional particle size reduction devices, such as oscillators or fitt mills, can be employed.

The dry granules are then placed in a suitable mixer, such as a twin-shell mixer, and the lubricant, semi-adhesive and all additional carrier materials are added. Although the mixing time depends in part on the process equipment used, a mixing time of at least about 5 to 25 minutes is generally preferred. In a preferred embodiment of this stage of the invention, the remainder of the talc and microcrystalline cellulose is mixed for an additional period, preferably for a period sufficient to achieve mixing uniformity for standard deviation values of less than about 6% and Is added to the granules.

Next, magnesium stearate is added to the mixture and the mixture is mixed uniformly for an additional time period. As mentioned above, when the diluent comprises microcrystalline cellulose, it has been found that during this step the addition of microcrystalline cellulose substantially increases the tablet strength. In addition, increasing the amount of magnesium stearate has been observed to reduce tablet strength and increase wear and disintegration time.

This homogeneous mixture is then compressed into the tablet (or encapsulated if a capsule is to be prepared) at the desired weight and strength using suitable size extensions. Conventional compression and encapsulation techniques known to those of ordinary skill in the art may be employed. If coated tablets are desired, conventional coating techniques known to those skilled in the art may be employed.

In the drawings forming part of the specification, FIG. 1, shown in two parts, FIGS. 1A and 1B, is a schematic diagram of a method of making a composition in accordance with the present invention.

The following examples illustrate aspects of the invention but are not to be construed as limiting. The experimental procedure used to generate the data shown is described in more detail below. The symbols and conventions used in these examples are consistent with those used in contemporary pharmaceutical literature. Unless stated otherwise, (iii) all percentages mentioned in these examples are weight percent based on the total composition weight, (ii) the total composition weight for the capsule is the total capsule fill weight and the capacity is the weight of the actual capsule adopted. does not contain, and (ⅲ) coated tablets are opadry ^® white YS-1-1802A (or other color) is coated with a conventional coating material such as a coating agent weight fraction is about 3% of the total weight of the coated tablet .

Example 1: 25 Mg Dose Immediate Release Tablet

A 25 mg dose immediate release tablet (tablet diameter 7/32 ") was prepared with the following composition.

ingredient Tablet (% by weight) Amount (mg) Eplerenon 29.41 25.00 Lactose Monohydrate (# 310, NF) 42.00 35.70 Microcrystalline Cellulose (NF, Avicel ^® PH101) 18.09 (10.59% extragranular with 7.50% in granules) 15.38 Croscarmellose Sodium (NF, Ac-Di-Sol ^TM ) 5.00 4.25 Hydroxymethylcellulose (# 2910, USP, Pharmacoat ^TM 603) 3.00 2.55 Sodium Lauryl Sulfate (NF) 1.00 0.85 Talc (USP) 1.00 0.85 Magnesium Stearate (NF) 0.50 0.42 Total amount 100 85 Opadry ^® white YS-1-18027A (optional: Opadry ^® yellow YS-1-12524-A) 3.00                                              (4.50) 2.55                                              (3.825)

The lactose monohydrates used in each of the examples herein are commercially available at Wisconsin, Barabu, Pomost Farm. Microcrystalline cellulose under the Avicel ^® brand and croscarmellose sodium under the Ac-Di-Sol ^™ brand were used in each of the examples herein. Both compounds are commercially available from Illinois, FMC Corporation. Hydroxypropyl methylcellulose under the Pharmacout ^™ 603 brand name was used in each of the examples herein. Such compounds are commercially available from Sin-Etsu Chemical Co., Ltd. Sodium lauryl sulfate used in each of the examples herein is commercially available from Ohio, Cincinnati, Henkel Corporation. Talc used in each of the examples herein is commercially available from North Carolina, Kings Mountain, Cyprus Foot Mineral Corporation, or Colorado, Inglewood, Luzenac Americas. Magnesium stearate used in each of the examples herein is commercially available from Missouri, St. Louis, Malincroft. Opadry ^® White YS-1-18027A (and other coatings) used to prepare the coated tablets disclosed in the Examples herein easily covers coating formulations commercially available from Pennsylvania, West Point, Colorcon.

Example 2: 50 Mg Dose Immediate Release Tablet

A 50 mg dose immediate release tablet (tablet diameter 9/32 ") was prepared with the following composition.

ingredient Tablet (% by weight) Amount (mg) Eplerenon 29.41 50.00 Lactose Monohydrate (# 310, NF) 42.00 71.40 Microcrystalline Cellulose (NF, Avicel ^® PH101) 18.09 (7.50% in granules and 10.59% in granules) 30.75 Croscarmellose Sodium (NF, Ac-Di-Sol ^TM ) 5.00 8.50 Hydroxypropyl Methylcellulose (# 2910, USP, Pharmacoat ^TM 603) 3.00 5.10 Natsu lauryl sulfate (NF) 1.00 1.70 Talc (USP) 1.00 1.70 Magnesium Stearate (NF) 0.50 0.85 Total amount 100 100 Opadry ^® white YS-1-18027A (optional: Opadry ^® pink YS-1-14762-A) 3.00                                              (3.00) 5.10                                              (5.10)

Example 3: 100 Mg Dose Immediate Release Tablet

A 100 mg dose immediate release tablet formulation (tablet diameter 12/32 ") was prepared with the following composition.

ingredient Tablet (% by weight) Amount (mg) Eplerenon 29.41 100.00 Lactose Monohydrate (# 310, NF) 42.00 142.80 Microcrystalline Cellulose (NF, Avicel ^® PH101) 18.09 (7.50% in granules and 10.59% in granules) 61.50 Croscarmellose Sodium (NF, Ac-Di-Sol ^TM ) 5.00 17.00 Hydroxypropyl Methylcellulose (# 2910, USP, Pharmacoat ^TM 603) 3.00 10.20 Sodium Lauryl Sulfate (NF) 1.00 3.40 Talc (USP) 1.00 3.40 Magnesium Stearate (NF) 0.50 1.70 Total amount 100 340 Opadry ^® white YS-1-18027A (optional: Opadry ^® red YS-1-15585-A) 3.00                                              (3.00) 10.20                                              (10.20)

Example 4: 10 Mg Dose Immediate Release Capsule

10 mg dose immediate release capsule formulations were prepared with the following compositions.

ingredient Tablet (% by weight) Amount (mg) Eplerenon 10.0 1.00 Lactose, Hydrous NF 306.8 30.68 Microcrystalline Cellulose, NF 60.0 6.00 Talc, USP 10.0 1.00 Croscarmellose Sodium, NF 8.0 0.80 Sodium Lauryl Sulfate, NF 2.0 0.20 Colloidal Silicon Dioxide, NF 2.0 0.20 Magnesium Stearate, NF 1.2 0.12 Total Capsule Fill Weight 400 40.00 Hard Gelatin Capsule, Size # 0, 1 capsule 100,000 capsules Sodium Lauryl Sulfate, NF 2.0 0.20 Colloidal Silicon Dioxide, NF 2.0 0.20 Magnesium Stearate, NF 1.2 0.12 Total Capsule Fill Weight 400.0 40.00 Hard Gelatin Capsule, Size # 0, White Opaque 1 capsule 100,000 capsules

Example 5 : 25 mg dose immediate release capsule

25 mg dose immediate release capsule formulations were prepared with the following compositions.

                                  ingredient Tablet (% by weight) Amount (mg) Eplerenon 25.0 2.50 Lactose, Hydrous NF 294.1 29.41 Microcrystalline Cellulose, NF 57.7 5.77 Talc, USP 10.0 1.00 Croscarmellose Sodium, NF 8.0 0.80 Sodium Lauryl Sulfate, NF 2.0 0.20 Colloidal Silicon Dioxide, NF 2.0 0.20 Magnesium Stearate, NF 1.2 0.12 Total Capsule Fill Weight 400.0 40.00 Hard Gelatin Capsule, Size # 0, White Opaque 1 capsule 100,000 capsules

Example 6: 50 mg dose immediate release capsule

50 mg dose immediate release capsule formulations were prepared with the following compositions.

ingredient Tablet (% by weight) Amount (mg) Eplerenon 50.0 5.00 Lactose, Hydrous NF 273.2 27.32 Microcrystalline Cellulose, NF 53.6 5.36 Talc, USP 10.0 1.00 Croscarmellose Sodium, NF 8.0 0.80 Sodium Lauryl Sulfate, NF 2.0 0.20 Colloidal Silicon Dioxide, NF 2.0 0.20 Magnesium Stearate, NF 1.2 0.12 Total Capsule Fill Weight 400.0 40.00 Hard Gelatin Capsule, Size # 0, White Opaque 1 capsule 100,000 capsules

Example 7: 100 mg dose immediate release capsule

100 mg dose immediate release capsule formulations were prepared with the following compositions.

ingredient Tablet (% by weight) Amount (mg) Eplerenon 100.0 10.00 Lactose, Hydrous NF 231.4 23.14 Microcrystalline Cellulose, NF 45.4 4.54 Talc, USP 10.0 1.00 Croscarmellose Sodium, NF 8.0 0.80 Sodium Lauryl Sulfate, NF 2.0 0.20 Colloidal Silicon Dioxide, NF 2.0 0.20 Magnesium Stearate, NF 1.2 0.12 Total Capsule Fill Weight 400.0 40.00 Hard Gelatin Capsule, Size # 0, White Opaque 1 capsule 100,000 capsules

Example 8: 200 mg dose immediate release capsule

200 mg dose immediate release capsule formulations were prepared with the following compositions.

ingredient Tablet (% by weight) Amount (mg) Eplerenon 200.0 20.00 Lactose, Hydrous NF 147.8 14.78 Microcrystalline Cellulose, NF 29.0 2.90 Talc, USP 10.0 1.00 Croscarmellose Sodium, NF 8.0 0.80 Sodium Lauryl Sulfate, NF 2.0 0.20 Colloidal Silicon Dioxide, NF 2.0 0.20 Magnesium Stearate, NF 1.2 0.12 Total Capsule Fill Weight 400.0 40.00 Hard Gelatin Capsule, Size # 0, White Opaque 1 capsule 100,000 capsules

Example 9: Oral Solution

The series of oral solutions contained 2.5 mg / L of eplerenone and the following components: ethanol v / v up to 20%; Propylene glycol v / v up to 10%; About 10% to 70% glycerol v / v; And water v / v of about 30% to 70%.

Another series of oral solutions were prepared containing 2.5 mg / L of eplerenone and further comprising ethanol, propylene glycol, polyethylene glycol 400, glycerin and 70% w / w sorbitol.

Other oral solutions were prepared in the following manner. 15% hydroxypropyl-β-cyclodextrin solution (20 mL) was added to the jar containing eplerenone (100 mg). The bottle containing the mixture was placed in a temperature controlled water bath / shaker at 65 ° C. and shaken for 20 minutes. The bottle was removed from the water bath and cooled for about 5 minutes at room temperature. Apple juice (60 mL, commercially available) was added to the mixture in the jar and the contents of the jar was gently stirred.

The oral solution of this embodiment is particularly useful for treating non-outpatients, pediatric patients and patients having difficulty taking solid dosage forms such as tablets and capsules.

Example 10 Tablets

Tablets containing a 100 mg dose of eplerenone and having the composition described in Table 10A were prepared by wet granulation (total batch size of 70 g). This 100 mg dose tablet had an average disintegration time of about 16 minutes and an average tablet strength of about 16 kP to 17 kP.

ingredient Weight fraction (%) Eplerenon 30.0 Lactose, Hydrous 25.0 Avicel ^® , PH101 37.5 Ac-Di-Sol ^TM 2.0 Pharmacout ^TM 603 3.0 Sodium Lauryl Sulfate, NF 1.0 Talc 1.0 Magnesium stearate 0.5 gun 100

The composition described in Table 10A was modified by adjusting the Ac-Di-Sol ^™ weight fraction of the seed from 2% to 5% value, while maintaining the weight fraction of Lactose / Avicel ^® at 25 / 37.5. Tablets containing this modified composition with 100 mg dose of eplerenone were prepared by wet granulation (total batch size of 70 g). Average disintegration results for these 100 mg dose tablets are reported in Table 10B below. Increasing the Ac-Di-Sol ^™ weight fraction to 5% resulted in a reduction in disintegration time of more than 10 minutes where no other changes were made to the composition.

Ac-Di-Sol ^TM weight fraction (%) Disintegration time (minutes) 2 14.11 ± 0.74 3 13.90 ± 0.34 4 13.84 ± 0.62 5 6.88 ± 0.48

The composition is then disintegrated with the addition of a disintegrant into the granules (ie, the component is present in the mixture during the wet granulation step) as well as extragranular (ie, the component is added after the wet granulated mixture is dried). It is further modified as described in Table 10C to increase the effect on ^® the weight fraction of lactose / Avicel for these compositions also was adjusted about 43 / 17.5 to about 45 / 17.5 to increase the compressibility of the composition. Tablets containing 100 mg dose of eplerenone and having this modified composition were prepared by wet granulation (total batch size of 70 g). The average disintegration results of these 100 mg dose tablets are reported in Table 10C below. Addition of 5% Ac-Di-Sol ^TM or 1.5% Ac-Di-Sol ^TM granules / 1.5% Ac-Di-Sol ^TM granules and 10% Avicel ^® have a disintegration time of about 7 to 9 minutes. Improved. The sodium starch glycorate of the Exploptab ^TM brand used in the composition is commercially available from Mendel.

Disintegration weight fraction (%) Disintegration time (minutes) In 2% Ac-Di-Sol ^{TM *} 12.6 ± 0.49 2% Ac-Di-Sol ^TM / 1% Ac-Di-Sol ^TM etc ^*  9.98 ± 1.15 1.5% Ac-Di-Sol ^TM / 1.5% Ac-Di-Sol ^TM etc  11.98 ± 0.54 2% Ac-Di-Sol ^TM / 2% Ac-Di-Sol ^TM etc  9.96 ± 0.31 4% Ac-Di-Sol ^TM / 1% Ac-Di-Sol ^TM etc  8.36 ± 0.64 1% sodium lauryl sulfate solution referred to within 4% Ac-Di-Sol ^TM my / 1% Ac-Di-Sol TM et al.  8.48 ± 0.53 In 2% Explortab ^TM 17.32 ± 0.71 1.5% Ac-Di-Sol ^TM / 1.5% Ac-Di-Sol ^TM etc  12.38 ± 0.41 1.5% Ac-Di-Sol ^TM I / 1.5% Ac-Di-Sol ^TM et al. / 10% Avicel ^® solution  7.90 ± 0.53

^{* In} = in granules; Et = extragranular.

The batch size for the 1% Ac-Di-Sol ^TM granules / 1% 5% Ac-Di-Sol ^TM extragranular composition and the 5% Ac-Di-Sol ^TM intragranular composition described above weighs from 70 g to 2 kg Went out. Tablets containing 100 mg of eplerenone and having this composition were prepared by wet granulation. The results for this 100 mg dose tablet are reported in Table 10D below. The term "granulation time" as used in this example and throughout the other examples herein means the total time after water addition and addition mixing.

Measured parameters 70g arrangement (2% Ac-Di-Sol TM I ^{* / 1% Ac-Di-} Sol TM et al. ^*) 2kg batch (2% Ac-Di-Sol TM I ^{* / 1% Ac-Di-} Sol TM et al. ^*) 2kg batch (5% Ac-Di-Sol TM I ^*) % Added water 35 27.48 40.82 Granulation time (minutes) 5.16 5.16 5.00 Drying time (minutes) 32 23 30 Moisture content (%) 2.0 2.15 2.2 Granule density (g / cc) 0.55 0.632 0.62 Tablet strength (kP) 16.57 9.41 10.27 Tablet thickness (mm) 4.38 4.39 4.33 Wear and tear% 0.357 0.264 - Disintegration time (minutes) - 12.86 9.15

^* See Table 10C.

Reduced tablet strength was observed for tablets made from 2 kg batches as compared to tablets made from 70 kg batches. In consideration of this decrease in tablet strength, 5% Ac-Di-Sol TM granules within the composition was removed with 10% Avicel ^® granules within and modified by replacing it with 10% extragranular Avicel ^®. Includes a plug fluorenone in the 100mg dose and 5% Ac-Di-Sol ^TM granules within the composition or the 5% Ac-Di-Sol ^TM granules within the granule within /7.5% Avicel ^® / 10% extragranular Avicel composition having a wet tablet Prepared by granulation (total batch size of 2 kg). Experimental results for this 100 mg dose tablet are reported in Table 10E below. Removing 10% intragranular microcrystalline cellulose and replacing it with 10% extragranular microcrystalline cellulose would result in (i) reduced density, (ii) increased tablet strength, (i) reduced disintegration time for the wet granulation step, And (iii) the reduced water demand.

Measured parameters 2 kg batch (in 5% Ac-Di-Sol ^TM ) 2kg batch (the outer 5% Ac-Di-Sol ^TM my / 10% Avicel ^{® *)} % Added water 40.82 36.59 Granulation time (minutes) 5 4.5 Coarse density (g / cc) 0.62 0.535 Tablet strength (kP) 11 (low compression force), 11 (high compression force) 14.5 (low compression), 18 (high compression) Disintegration time (minutes) 9.15 6.31

^* See Table 10C.

A 5% 1.5% Ac-Di-Sol ^™ intragranular / 7.5% intragranular Avicel ^® / 10% extragranular Avicel ^® composition was prepared as described in Table 10F. Tablets containing this 100 mg dose of efullene and having this composition were prepared by wet granulation (total batch sizes of 2 kg and 10 kg).

ingredient Weight fraction (%) Eplerenon 30 Lactose, Hydrous 42 Avicel ^® , PH101 7.5 out of 10 Ac-Di-Sol ^TM 5 Pharmacout ^TM 603 3 Sodium Lauryl Sulfate, NF One Talc One Magnesium stearate 0.5 gun 100

^* See Table 10C.

Experimental results for these 100 mg dose tablets are reported in Table 10G below. Scale-up of this formulation is achieved without a drop in tablet strength, while maintaining a disintegration time of about 7 minutes.                 

Measured parameters 2 kg batch 10 kg batch % Added water 36.59 30.52 Granulation time (minutes) 4.5 5.25 Drying time (minutes) 32 11 Granule density (g / cc) 27 0.549 Tablet strength (kP) 11.71 12.84 Tablet thickness (mm) 4.47 4.37 Wear and tear% 0.223 0.38 Disintegration time (minutes) 6.31 7.00

Example 11: Two Hour Adjusted Release Tablets

A controlled release tablet (tablet weight 333.3 mg; round, standard, concave, 12/32 ") containing 100 mg dose of eplerenone was prepared. The tablet has the following composition.

ingredient Tablet (% by weight) Eplerenon 30.0 Lactose Monohydrate 40.0 Microcrystalline Cellulose (AVICEL ^® PH 101) 19.5 Hydroxymethylcellulose (Methocel ^® K4M Pyridium) 6.0 Hydroxypropyl Methylcellulose (Pharmacout ^TM 603) 3.0 Talc 1.0 Magnesium stearate 0.5 gun 100

Example 12 Four Hour Adjusted Release Tablet

Adjusted release tablets (round standard concave) were prepared comprising 50 mg (9/32 "), 100 mg (12/32") and 150 mg (14/32 ") doses of Eplerenone. Has                 

ingredient Tablets (% by weight) 50 mg 100 mg 150 mg Eplerenon 30.0 30.0 30.0 Lactose Monohydrate 27.0 35.7 37.0 Microcrystalline Cellulose (AVICEL ^® PH 101) 13.5 17.8 18.5 Hydroxymethylcellulose (Methocel ^® K4M Pyridium) 25.0 12.0 10.0 Hydroxypropyl Methylcellulose (Pharmacout ^TM 603) 3.0 3.0 3.0 Talc 1.0 1.0 1.0 Magnesium stearate 0.5 0.5 0.5 gun 100 100 100

Example 13: Six hour adjusted release tablet

A controlled release tablet (tablet weight 333.3 mg; round, standard, concave, 12/32 ") containing 100 mg dose of eplerenone was prepared. The tablet has the following composition.

ingredient Tablet (% by weight) Eplerenon 30.0 Lactose Monohydrate 30.5 Microcrystalline Cellulose (AVICEL ^® PH 101) 15.0 Hydroxymethylcellulose (Methocel ^® K4M Pyridium) 20.0 Hydroxypropyl Methylcellulose (Pharmacout ^TM 603) 3.0 Talc 1.0 Magnesium stearate 0.5 gun 100

Example 14 Tablet

Tablets containing 100 mg dose or 200 mg dose of eplerenone and having one of the compositions described in Table 14A were prepared by wet granules (total batch size of 1 kg). In addition, tablets containing Formulation C, shown in Table 14A, containing either 100 mg or 200 mg doses of eplerenone were prepared by wet granulation (total batch size of 2 kg).

ingredient Weight fraction of tablets (%) A B C D E F Eplerenon 30 30 30 30 30 30 Lactose Monohydrate 10 40 10 40 25 25 Microcrystalline Cellulose (AVICEL ^® PH 101) 50.5 20.5 35.5 5.5 28 28 Hydroxymethylcellulose (Methocel ^® K4M Premium) 5 5 20 20 12.5 12.5 Hydroxypropyl Methylcellulose (Pharmacout ^TM 603) 3 3 3 3 3 3 Talc One One One One One One Magnesium stearate 0.5 0.5 0.5 0.5 0.5 0.5 gun 100 100 100 100 100 100

Tablets made from 2 kg batches (Formulation C) showed a loss of tablet strength and compressibility compared to tablets made from 1 kg batches (Formulation C). The average tablet strength for the 100 mg dose tablets prepared in the 2 kg batch was about 7 kP. The average tablet strength for a 200 mg dose tablet made in a 1 kg batch was about 9 kP. It is noted that in place of comparison, placebo granules with a high microcrystalline cellulose weight fraction (eg, about 65.5%) were not compressed into tablets. For 2 kg batches, a granulation time of about 10 to 12 minutes resulted in increased water loss due to evaporation during granulation compared to 1 kg batches.

Purification was Article so as to have the composition of the next to include the plug fluorenone and 100mg dose of the composition or formulation is lactose and Avicel ^® the weight fraction of the formulation C against C. Tablets were prepared by wet granulation using different granulation times (total batch size of 70 g). Tablet compression was performed on an F3 single punch compressor. As shown in Table 14B below, the longer granular time and the combination of higher microcrystalline cellulose content resulted in a loss of strength. Sensitivity to the granular state was reduced when the lactose / microcrystalline cellulose ratio was adjusted from 10 / 35.5 to 30.5 / 15.

Lactose / Avicel ^® Ratio Moisture content (%) Strength (kP) Wear and tear (%) Granular Time ^* (min) 10 / 35.5 1.37 17.84 0.1783 5 (single-stage water addition) 10 / 35.5 2.65 10.65 0.846 6.5 (add multi-step water) 10 / 35.5 3.2 18.75 0.230 4.6 (single-stage water addition) 30.5 / 15 One 16.18 0.1047 4.1 (single-stage water addition) 30.5 / 15 2.01 15.90 0.0824 3.85 (single-stage water addition) 30.5 / 15 3.95 15.77 0.2947 4.46 (single-stage water addition) 30.5 / 15 1.12 14.86 0.365 4.13 (single-stage water addition) 30.5 / 15 2.57 14.41 0.263 6.91 (single-stage water addition) 30.5 / 15 1.99 14.28 0.243 6.91 (with multi-stage water)

^* Granular time = water addition + post-mixing time.

Modified release (“CR”) tablets containing 100 mg dose of eplerenone and having one of the compositions described in Table 14C below were prepared by wet granulation (70 g total batch size). The in vitro mean dissolution time in 1% SDS in water for each composition was then measured. The 2 hour 100 mg dose CR tablet was 37% dissolved at 2 hours. The 4 hour 100 mg dose CR tablet was 42% dissolved at 4 hours. The 6 hour 100 mg dose CR tablet was 54% dissolved at 6 hours.

ingredient Weight% of tablet 2 hours CR 4 hours CR 6 hours CR Eplerenon 30 30 30 Lactose Monohydrate 40 36 30.5 Microcrystalline Cellulose (AVICEL ^® PH 101) 17.5 15.5 15 Hydroxypropyl Methylcellulose (Methocel ^® K4M Premium) 8 14 20 Hydroxypropyl Methylcellulose (Pharmacout ^TM 603) 3 3 3 Talc One One One Magnesium stearate 0.5 0.5 0.5 gun 100 100 100

Two-hour CR, four-hour CR, and six-hour CR tablets containing 100 mg dose of eplerenone were prepared by wet granules during the scale-up process (total batch sizes of 2 kg and 10 kg). Tablets are the high molecular weight hydroxypropyl methylcellulose (Methocel ^® K4M Premium) weight fractions, and microcrystalline cellulose weight fractions of 19.5% and 17.5% respectively of 6% and 12% 2 hours CR and 4 hours CR tablet compositions each Had the same composition as described in Table 14C above. Tablets 14D, 14E and 14F report experimental results. The dissolution profile can be further adjusted by appropriate choice of high molecular weight hydroxypropyl methylcellulose concentration. In addition, the dissolution time decreases with increasing hydroxypropyl methylcellulose particle size. This may be due to poor hydration of the hydroxypropyl methylcellulose substrate as the particle size increases. Smaller particle sizes, on the other hand, result in faster hydration of the substrate, resulting in slower drug release rates.

 Measured parameters 2 hour CR tablet (100 mg dose) 70 g batch ¹ 2 kg batch 10 kg batch % Added water 38.57 30.71 29.71 Granular time (minutes) 4.00 4.07 4.00 Drying time (minutes) 60 30 11 Moisture content (%) 2.0 1.28 1.62 Granule density (g / cc) 0.55 0.58 0.63 Tablet strength (kP) 14.05 13.79 11.37 Tablet thickness (mm) 4.58 4.40 4.4 Wear and tear% 0.351 0.263 0.39

^One tablet made in a 70 g batch had the composition described in Table 14C.

 Measured parameters 4 hour CR tablet (100 mg dose) 70 g batch ¹ 2 kg batch 10 kg batch % Added water 41.42 29.67 31.26 Granular time (minutes) 4.00 4.25 6.25 Drying time (minutes) 45 27 11 Moisture content (%) 1.2 2.21 1.18 Granule density (g / cc) 0.536 0.513 0.60 Tablet strength (kP) 14.8 11.5 12.4 Tablet thickness (mm) 4.59 4.43 4.58 Wear and tear% 0.219 0.323 0.213

^One tablet made in a 70 g batch had the composition described in Table 14C.

 Measured parameters 6 hour CR tablet (100 mg dose) 70 g batch ¹ 2 kg batch 10 kg batch % Added water 45.71 37.73 35.35 Granular time (minutes) 4.13 4.00 5.5 Drying time (minutes) 45 35 12 Moisture content (%) 1.12 1.4 0.68 Granule density (g / cc) 0.523 0.536 0.561 Tablet strength (kP) 14.9 13.7 12.4 Tablet thickness (mm) 4.64 4.56 4.58 Wear and tear% 0.365 0.141 0.12

Compositions comprising various amounts of hydroxypropyl methylcellulose (HPMC) were prepared, compressed to different tablet sizes and evaluated during dissolution time. The hydroxypropyl methylcellulose weight fractions of each composition are shown in Tables 14G and 14H below. Eplelenone, Pharmacout ^™ 603, talc and magnesium stearate weight fractions were fixed at 30%, 3%, 1%, and 0.5%, respectively. The ratio of lactose / microcrystalline cellulose was fixed at 2: 1 and the amount of lactose and microcrystalline cellulose was adjusted to adapt to the hydroxypropyl methylcellulose (HPMC) concentration. Tables 14G and 14H below reported the average dissolution results in 1% SDS for the composition. Table 14G records the approximate time that tablets achieve 50% in vitro dissolution, while Table 14H records in vitro dissolution in 1% SDS at 24 hours. In general, the dissolution rate increased as the tablet size decreased and / or as the tablet shape changed from the standard circle to the caplet shape.

 Capacity (Punch Size) Approximate time (in hours) of 50% dissolution in vitro 6% HPMC 15% HPMC 25% HPMC 35% HPMC 45% HPMC 25mg (7/32 ") --- --- 3.12 4.35 5.78 62mg (10/32 ") --- 4.00 --- 7.54 100mg (12/32 ") 2.41 --- 5.88 --- 4.24 125mg (13/32 ") --- 5.5 --- 21.33 --- 150mg (14/32 ") 4.11 3.00 16.62 --- ---

 Capacity (Punch Size) % Dissolution at 24 hours 6% HPMC 15% HPMC 25% HPMC 35% HPMC 45% HPMC 25mg (7/32 ") --- --- 107 102 5.78 62mg (10/32 ") --- 98 --- 86 7.54 100mg (12/32 ") 104 --- 68 --- 4.24 125mg (13/32 ") --- 83 --- 52 --- 150mg (14/32 ") 101 131 56 --- ---

Table 14I The results of Table 14G above are further summarized for the 4 hour CR composition. Based on experimental data, hydroxypropyl methylcellulose (HPMC) concentrations of 35%, 25%, 12%, and 10% were achieved to achieve 50% dissolution in vitro in 1% SDS time (DT ₅₀ ) of about 4 hours. For the 25 mg, 50 mg, 100 mg and 150 mg eplerenone doses.

Eplerenone dose (mg) HPMC weight fraction (%) Punch Size (Round, SC) Tablet weight (mg) DT ₅₀ = Emission for 4 Hours 25 30 7/32 " 83.3 furnace 25 35 7/32 " 83.3 Yes 50 20 9/32 " 166.6 furnace 50 25 9/32 " 166.6 Yes 100 12 12/32 " 333.3 Yes 150 6 14/32 " 500 furnace 150 10 14/32 " 500 Yes

Example 15: Disintegration Test

Six identical tablets were each placed in one of six tubes with wire mesh screen bottoms in disintegrating baskets. The water bath was preheated to 37 ° C. ± 2 ° C. and maintained at that temperature within the disintegration curve. 1000 mL beakers were placed in a water bath. The beaker was filled with a sufficient amount of water to ensure that the wire mesh screen of the tube was kept at least 2.5 cm below the water surface during the test. Disintegrating beakers were placed in water at a temperature of 0 min and repeatedly raised and lowered until the test was completed, while maintaining the wire mesh screen of the tube at least 2.5 cm below the water surface. The disintegration time for each tablet was the time when the last part of the tablet passed through the screen at the bottom of the tube. The average result for each type of tablet test is reported in Table 15.

refine Disintegration time Example 1: 25 mg dose tablet (coated) 8 minutes, 6 seconds Example 1: 25 mg dose tablet (uncoated) 6 minutes, 16 seconds Example 2: 50 mg dose tablet (coated) 9 minutes, 17 seconds Example 2: 50 mg dose tablet (uncoated) 7 minutes, 39 seconds Example 3: 100 mg dose tablets (coated) 10 minutes, 30 seconds Example 3: 100 mg dose tablets (uncoated) 8 minutes, 24 seconds

Example 16: Immediate Release Dissolution Test

U.S.P. The device of II (with paddle) was used to determine the dissolution rate in 1% SDS of the tablets of Examples 1, 2, and 3 for coated and uncoated immediate release tablets. 1000 mL 1% sodium lauryl sulfate (SDS) / 99% aqueous solution was used as the dissolution fluid. The solution was maintained at a temperature of 37 ° C. ± 0.5 ° C. and stirred at 50 rpm during the test. Twelve identical tablets were tested. Twelve tablets were each placed separately in one of the twelve standard dissolution vessels at time = 0 minutes. At times = 15, 30, 45 and 60 minutes, the 5 mL fractionated solution was removed from each vessel. Each vessel sample was filtered and the absorbance of the sample was measured (UV spectrophotometer; 2 mm path length quartz cell; 243 nm or UV maximum wavelength; blank; solvent medium). Percent dissolution was calculated based on the measured absorbance. The results of the dissolution test are reported in Table 16A.

 refine % Dissolution at several minutes 15 30 45 60 Example 1: 25 mg dose tablet (coated) 92 99 100 101 Example 1: 25 mg dose tablet (uncoated) 92 98 99 99 Example 2: 50 mg dose tablet (coated) 90 100 102 103 Example 2: 50 mg dose tablet (uncoated) 89 97 98 98 Example 3: 100 mg dose tablet (coated) 82 95 97 98 Example 3: 100 mg dose tablets (uncoated) 84 94 96 96

Similar studies were conducted using 100 mg coated tablets prepared as described in Example 3, where eplerenones, as in Example 3, had 45 micron D ₉₀ particle sizes, 165 microns and 227 microns. Have Six tablets were used for each study rather than the twelve described above. The results of such a study are shown in Table 16B below. The particle size distribution of these three samples is shown in Table 16C below.

 refine % Dissolution at various minutes 15 30 45 60 90 Example 3: D ₉₀ = 45 microns 69 87 93 95 97 Example 3: D ₉₀ = 165 microns 57 80 90 95 102 Example 3: D ₉₀ = 227 microns 47 69 80 87 100

Size distribution of finely divided eplerenone particles in microns D _value D ₉₀ = 45 D ₉₀ = 165 D ₉₀ = 227 D ₅ 1.7 4 6.5 D ₁₀ 2.7 9 18 D ₅₀ 13.3 75 102 D ₇₅ 27 119 164 D ₉₀ 44.7 165 227 D ₉₅ 58.3 196 265

Example 17: Adjusted Release Dissolution Test

The procedure of Example 16 using 1% SDS was followed to test the 100 mg dose adjusted release tablets of Examples 11 and 13 and the 50 mg, 100 mg and 150 mg dose adjusted release tablets of Example 12. The average results of the dissolution test are reported in Table 17.

Dissolution(%)  Hour 2 hour CR tablets (Example 11: 100 mg dose) 4-hour CR purification (Example 12) 6 hour CR tablets (Example 13: 100 mg dose) 50 mg dose 100 mg dose 150mg dose 0.5 5 6 7 7 4 One 8 12 13 13 7 2 18 25 27 26 15 3 29 38 40 39 24 4 48 51 53 51 33 6 86 74 74 71 49 8 100 87 91 87 64 9 - 97 101 100 - 24 104 - - - 105

Example 18 Particle Size Analysis

Table 18 shows the results of particle size sieve analysis of small scale wet granulated batches of the pharmaceutical compositions of Examples 1, 11, 12 and 13 before being compressed into tablets. "Accumulated percent of batch" refers to the percentage of the total batch having a particle size larger than the indicated sieve size.

Cumulative Percent of Batch Sieve size (microns) IR ^* (Example 1 Composition) 2 hour CR (Example 11 composition) 4 hour CR (Example 12 composition-100 mg dose) 6 hour CR (Example 13 composition) minuteness 100.00 100.00 100.00 100.0 63 (230 mesh screen) 91.13 88.68 88.37 84.11 106 (140 mesh screen) 79.97 76.53 70.92 68.26 180 (80 mesh screen) 57.10 65.71 52.88 51.12 250 (60 mesh screen) 35.19 57.81 42.62 41.58 300 (50 mesh screen) 22.54 51.64 36.34 35.07 425 (40 mesh screen) 8.85 40.60 27.31 26.21

^* IR = immediate release; CR = adjusted release.

Example 19 Large Density Analysis

Table 19 shows the average results for trade density analysis of several small scale wet granulated batches of the pharmaceutical compositions of Examples 1, 11, 12 and 13 before being compressed into tablets.

Composition Trading Density (g / mL ³ ) Example 1: Immediate Release 0.568 Example 11: 2-hour adjusted release 0.622 Example 11: 4-hour adjusted release 0.565 Example 1: 4-hour adjusted release 0.473 Example 1: 4-hour adjusted release 0.487 Example 1: 4-hour adjusted release 0.468 Example 1: 6 hour adjusted release 0.528

Example 20 Purification Assay Program

Table 20 shows a tablet analysis program ("TAP assay") for sampling of tablets with the compositions of the tablets of Examples 1, 2, 3, 11, 12, and 13.

Tablet tested (N = 10) Average weight (mg) Average thickness (mm) Strength (kP) Example 1: 25 mg dose (IR ^* , film coated) 88.5 3.3157 7.64 Example 1: 25 mg dose (IR, uncoated) 85.5 3.2845 4.55 Example 2: 50 mg dose (IR, uncoated) 170.5 4.0297 7.31 Example 2: 50 mg dose (IR, film coated) 176.0 4.093 10.95 Example 3: 100 mg dose (IR, uncoated) 340.7 4.4902 9.92 Example 3: 100 mg dose (IR, film coated) 349.6 4.546 13.91 Example 11: 100 mg dose (2 hours CR ^* ) 329.7 4.412 11.53 Example 12: 50 mg dose (4 hour CR) 160.0 4.1723 10.55 Example 12: 100 mg dose (4 hour CR) 331.4 4.6672 14.62 Example 12: 150 mg dose (4 hour CR) 498.7 5.4440 11.63 Example 13: 100 mg dose (6 hours CR) 335.1 4.8242 11.05

See Table 19 annotation.

Example 21 Wear Test

Twelve tablets were weighed and placed in a rotating drum. External dust was first removed from the drum and tablets. The drum was started and continued to rotate for 10 minutes at a minimum speed of 25 revolutions per minute. All tablets, as well as tablets, were dusted off and weighed intact. The percent loss of the test samples of Examples 1, 2, 3, 11, 12 and 13 was calculated and shown in Table 21 below.

refine Percent loss Example 1: 100 mg dose (IR ^* ) 0.177 Example 2: 50 mg dose (IR) 0.236 Example 3: 25 mg dose (IR) 0.000 Example 11: 100 mg dose (2 hours CR ^* ) 0.42 Example 12: 100 mg dose (4 hour CR) 0.33 Example 13: 100 mg dose (6 hours CR) 0.12

See note in Table 19.

Example 22 Preparation of Immediate Release Tablets

The components of the pharmaceutical compositions of the present invention may be prepared according to acceptable pharmaceutical manufacturing practices in the manner illustrated by the flow charts of FIGS. 1A and 1B for small scale preparation.

Exemplary formulation procedures using Table 22 are described below. The process can be performed as a single batch reaction or as one or more parallel batch reactions.

ingredient Weight of tablet (%) Amount of starting material (kg / batch) Eplerenon 29.41 4.412 Lactose Monohydrate (# 310, NF) 42.00 6.3 Microcrystalline cellulose (in granules) (NF, Avicel ^® PH 101) 7.50 1.125 Croscarmellose Sodium (NF, Ac-Di-Sol ^TM ) 5.00 0.75 Hydroxypropyl Methylcellulose (# 2910, USP, Pharmacout ^TM 603) 3.00 0.45 Sodium Lauryl Sulfate (NF) 1.00 0.15 Talc (USP) 1.00 0.15 Microcrystalline cellulose (out of granules) (NF, Avicel ^® PH 101) 10.59 1.588 Magnesium Stearate (NF) 0.50 0.075 gun 100.00 15.00

Grinding: Eplerenones were ground in a jet mill. The resulting ground eplerenones had D ₁₀ , D ₅ , and D ₉₀ values of 2.65 microns, 23.3 microns and 99.93 microns, respectively. That is, 10%, 50% and 90% of the eplerenone particles were 2.65 microns, 23.3 microns and 99.3 microns in size, respectively. Pin milling is preferred for production on a manufacturing scale.

Dry mix: A 65 L Niro ^TM filter granulator was charged in the order of lactose, eplerenone, Avicel ^® , Ac-Di-Sol ^TM , Pharmacout ^TM 603 and sodium lauryl sulfate. This material was mixed homogeneously (about 3 minutes) into the main blade on the slow main blade setting and the chopper blade on the slow chopper blade setting. For manufacturing scales, machines such as the Buckler Perkins ^™ 1000L granulator can be used.

Wet Granular: The dry powder mixture was granulated with USP water. The main blade and the chopper blade of the granulator were placed in the fast speed setting. 5 kg of water was added to the mixture over a period of about 3 minutes using a Masterflex ^™ water pump, Model 7524-00 (24 "tubing). The rate of water addition was about 1.66 kg / min. The wet hops were mixed for a few more minutes to ensure a uniform distribution, while the wet granulated mixture was about 38% water by weight.

Drying: The wet granules were placed in a Freund ^™ Flo-Cotter (FLF-15) Fluid Bed Dryer. The inlet air temperature was adjusted to about 68 ° C. and the granules were dried in a fluid bed dryer to reduce the water content between about 0.5% and 2.5%. Moisture content was monitored using a Computex ^™ Moisture Analyzer.

Dry Screening: The dry granules passed through a 20 # screen, forward knife, and a Pittss mill at 2400 rpm.

Mixing and Lubrication: The dry granules were then placed in a PK2 cubic foot V-mixer. Talc and extragranular Avicel ^® 101 were placed on top of the granules and the mixture was mixed homogeneously (about 10 minutes). Magnesium stearate was added to the top of the mixture and the mixture was mixed for an additional 3 minutes. Crop ^™ flow mixers can be used for large scale manufacturing.

Compression: The granules were then compressed on a Kilian ^TM table compressor at the desired weight and strength using a suitable size tool. Target weights, sizes and intensities for 25, 50, and 100 mg are shown in Table 22A below.

Dose of Eplerenone (mg) Tablet capacity (mg) Tool Size (Inches) (Round, Standard Concave) Target strength range (kP) 25 85 7/32 3-9 50 170 9/32 5-14 100 340 12/32 8-16

Film coating: Washing sterilization water was placed in a stainless steel container created with an electric mixer with a stainless steel impeller (Lightnin ^™ TSM 2500). The mixer was turned on at a suitable speed. Opadry ^® , white (YS-1-18027-A) was added slowly to the vortex while preventing bubbles from forming to provide a solution with an Opadry ^® : water weight ratio of 15:85. Mixing continued for an additional 30 minutes or until all material was dispersed and a uniform suspension was observed. Constantly slow stirring was maintained during the coating process. Coating of the tablets was carried out in a conventional manner using the Vector ^TM High Coater VHC-1355 equipped with a 35L coating pan with two spray guns.

Example 23 Preparation of a Modified Release Tablet

Exemplary formulation procedures with the starting materials in Table 23 are described below. The process can be performed by a single batch reaction or by two or more parallel batch reactions.

ingredient Weight of tablet (%) Amount of starting material (kg / batch) Eplerenon 30.0 3.0 Lactose Monohydrate 34.0 3.4 Microcrystalline Cellulose (AVICEL ^® PH 101) 19.5 1.95 Hydroxypropyl Methyl Cellulose (Mitocell ^® K4M Premium) 12.0 1.2 Hydroxypropyl Methylcellulose (Pharmacout ^TM 603) 3.0 0.3 Talc 1.0 0.1 Magnesium stearate 0.5 0.05 gun 100 10

Dry mix: 60L filled the Baker Perkins mixer ^TM in the order of lactose, plug fluorenone, Oh Vissel ^®, Mito cells ^® K4M, and perm Koh bit ^TM 603 to a fine powder. This material was mixed for 3 minutes into the main blade on the slow main blade setting and the chopper blade on the slow chopper blade setting.

Wet Granular: The dry powder mixture was wet granulated with USP water. The main blade and the chopper blade of the mixer were placed at high speed settings. About 3.1 kg of water was added to the mixture over a period of about 3 minutes using an Aeromatic ^™ water pump. The rate of water addition was about 995 g / min. The moist mixture was mixed for a few additional minutes to ensure a uniform distribution of water in the granules. The wet granulated mixture had a water weight ratio of about 31%.

Drying: The wet granules were placed in an Aeromatic ^™ Fluid Bed Dryer. The inlet air temperature was set at about 60 ° C. and the granules were dried in the fluid bed dryer to reduce the moisture content between 1% and 3%. The moisture content of the granules was monitored using kompyu track ^TM Moisture Analyzer.

Dry Screening: Dry granules were passed through a Pitts Mill (D6A) at 20 # screen, forward knife and medium speed (1500-2500 rpm). The ground granules were collected in a polyethylene bag.

Lubrication: The dry granules were placed in a PK 2 cubic foot V-mixer. Talc was placed on top of the granules and mixed for 5 minutes. Magnesium stearate was placed on top of the granules and mixed for 3 minutes. The granular phase was taken out of the mixer and transferred into a fiber drum aligned with a double polyethylene bag.

Compression: The granules 12/32 "round standard concave shape by using the tool has been compressed to the desired weight and strength Le Kosh ^TM tablet compressor target weight it was 333.3mg target strength was 11-13kP for 100mg tablets.

Film coating: USP water was added to a stainless steel container and mixed with a low speed electric mixer with stainless steel impeller. Opadry ^® (white: YS-1-18027-A) was added slowly to the vortex. The rate of whipping was increased as necessary to disperse Opadry ^® in water (10% Opadry / 90% water w / w) while preventing bubbles from forming. Mixing continued until all the material was dispersed and a uniform suspension was observed or for 30 minutes. The suspension was kept at a constant slow whisk during coating.

Coating: 36 "coating pan and the comb pulraep ^TM coater with gun single spray was used atomization air was set to 45psi of the required coating suspension was sprayed to obtain a 3% by weight obtained for the tablets Weigh the tablet The amount was determined The tablets were placed in a pan and the air flow was set at 700 cubic feet per minute The pan was shaken every 2 minutes to warm the tablets for about 10 minutes The inlet air temperature was set at 65 ° C. The temperature was about 45 ° C. The rotation of the fan at 10 rpm was started and the spray was started The spray rate was set at 50 g / min The process was monitored by checking and recording the coating parameters at each time interval. Continue until the required amount of coating suspension was sprayed and then stop spraying The fan rotation continued for an additional 2 to 5 minutes. The air heater was turned off and the fan rotation was stopped The tablets were allowed to cool for 10 minutes and the fans were shaken every 2 minutes during cooling Coated tablets were transferred from the coating pans to the fiber drums arranged in double polyethylene bags.

Example 24 Single Dose Safety and Pharmacokinetic Studies

The pharmacokinetics, stability and anti-aldosterone activity of single 10, 50, 100, 300 and 1000 mg oral doses of eplerenone were evaluated in a single-central, randomized, double-blind, placebo-adjusted study.

It has been determined that the plasma eplerenone is in equilibrium with the inertopen lactone ring form of the eplelenone. The pharmacokinetics of eplerenone in the form of this inactive open lactone ring was also evaluated. The study adopted seven matched dose groups of eight healthy men. Each subject was: (i) 10 mg dose of eplelenone (one 10 mg dose capsule), (ii) 50 mg dose of eplerenone (two 25 mg dose capsules), (iii) 100 mg dose of eplerenone ( One 100 mg dose capsule), (iii) 300 mg dose of eplerenone (three 100 mg dose capsules), (iii) 1000 mg dose of eplerenone (five 200 mg dose capsules), (iii) 50 mg dose of spironolactone , Or (iii) received a single dose of placebo. The pharmacokinetic profile was assessed using the measured blood and urine levels of epenolenone, eplerenone and spironolactone in the open lactone form.

Antialdosterone activity was determined based on urine levels of sodium and potassium following repeated administrations of fludrocortisone. Safety was determined based on laboratory testing, biomarkers, and the occurrence and type of history event.

Eplerenone capsules were administered correspondingly to the capsules described in Examples 4, 5, 7 and 8 (or combinations of such capsules). Placebo was a conventional capsule containing lactose. The spironolactone used in this study was obtained from Sear Canada (Oakville, Ontario). The Fludrocortizone used in this study consisted of commercially available Fludrocortizone tablets (Fluoroneph ^® , Squibb BV).

Subjects who fasted for 10 hours prior to dosing were given a single oral dose of one of the study medications with about 180 mL of water at 0800 hours. All subjects received a 1.0 mg dose of fludrocortisone 9 hours prior to administration of the drug of this study; 0.5 mg dose of fludrocortisone at the time of administration of the study drug; 0.1 mg dose of fludrocortisone at 2, 4, 6, 8, 10, 12 and 14 hours after administration of the study drug; A dose of 0.5 mg of fludrocortisone was given 16 hours after administration of the study drug. Each dose of fludrocortisone was administered with 150 mL of water except for the 1.0 mg dose administered with 200 mL of water.

12-lead ECG was obtained 2, 3, 4, and 24 hours after administration of the study drug and prior to dosing (within one hour). Body temperature (oral), rate of absorption and pulse rate and blood pressure (after sitting for 3 minutes) were 0.25, 0.5, 1, 2, 4, 8, 12, and 24 before and after the study drug and after administration Got in time. Blood samples were collected at −0.25 (before dose), 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 28, 32, 48, 72 and 96 hours post dose. Urine samples were subjected to the following cycles: -9 to 0; 0 to 2; 2 to 4; 4 to 6; 6 to 8; 8 to 10; 10 to 12; 12 to 14; 14 to 16; And 16-24 hours of collection.

Plasma samples collected from subjects taking the eplerenones were evaluated for the concentrations of the eplerenones and the form of the open lactone rings. Plasma samples of subjects taken with spironolactone were evaluated for concentrations of spironolactone and its metabolite canrenone, 7α-thiomethylspironolactone, and 6β-hydroxy-7α-thiomethylspironolactone. Small sets of plasma samples were also evaluated for testosterone levels. The collected urine was analyzed to determine the concentration and amount of eplerenone and the form of open lactone ring, the amount of sodium and potassium secreted, and the log ₁₀ (sodium / potassium) ratio of urine. Average results obtained from the tested subjects are shown in Tables 24A-24J below. There were no clinically significant changes in physical observations, signs of life or clinical results. All the stations were not bad.

Time after taking (hours) Eplerenone or spironolactone at plasma concentration (ng / mL) 10mg (Epl. *) 50mg (Epl.) 100mg (Epl.) 300mg (Epl.) 1000mg (Epl.) 50mg (Spi *) -0.25 0 0 0 0 0 0 0.5 130.4 552.5 758.0 1619.6 3176.3 10.5 1.0 177.0 720.6 1224.6 2676.3 5258.8 23.6 2.0 158.6 692.9 1363.8 2775.0 5940.0 14.4 3.0 125.4 591.5 1113.5 2225.0 6810.0 14.3 4.0 105.7 456.6 900.1 1951.3 6218.8 4.8 6.0 65.3 269.8 558.5 1266.6 4150.0 0 8.0 34.4 146.4 275.3 842.9 2827.5 0 12.0 6.0 49.4 124.3 333.0 1335.1 0 16.0 6.0 18.3 41.9 141.9 646.8 0 24.0 1.7 3.0 13.1 38.3 208.0 0 28.0 0 1.8 6.1 21.1 107.1 0 32.0 0 0 3.0 11.3 61.7 0 48.0 0 0 0 1.7 22.3 0 72.0 0 0 0 0 1.4 0 96.0 0 0 0 0 0 0

   * Epl. = Eplerenone; Spi. = Spironolactone.

The data demonstrated the primary relationship between the eplelenone dose and the plasma concentration for the estimated eplanenone dose.

Pharmacokinetic Parameters Pharmacokinetic parameter values (Epl. = Eplerenone) 10mg (Epl.) 50mg (Epl.) 100mg (Epl.) 300mg (Epl.) 1000mg (Epl.) AUC (0-96) [(ng / mL) hr] 941.5 4017.0 7943.4 18451.4 56435.3 C _max (μg / mL) 191.3 797.0 1505.0 2967.5 7261.3 T _max (hours) 1.3 1.4 1.5 1.5 2.5 T _1/2 (hours) 2.1 2.9 4.9 3.7 15.1 Average residence time (hours) 3.9 4.2 4.9 5.5 7.0 Oral Scavenging (L / hr) 13.3 13.7 13.1 17.6 18.4

Time after taking (hours) Plasma concentration of open ring lactone (ng / mL) 10mg (Epl.) ¹ 50mg (Epl.) 100mg (Epl.) 300mg (Epl.) 1000mg (Epl.) -0.25 0 0 0 0 0 0.5 1.2 24.3 33.9 123.0 191.3 1.0 1.2 34.5 50.3 203.2 359.9 2.0 0 27.1 48.8 177.9 405.8 3.0 0 22.5 40.3 141.4 453.3 4.0 0 17.5 30.6 116.7 392.3 6.0 0 9.5 19.0 74.0 285.3 8.0 0 3.3 6.5 45.1 167.9 12.0 0 0 0 15.3 73.7 16.0 0 0 0 2.1 63.9 24.0 0 0 0 0 8.3 28.0 0 0 0 0 3.2 32.0 0 0 0 0 1.8 48.0 0 0 0 0 0 72.0 0 0 0 0 0

¹ Maximum concentrations were under evaluation validation limits; Epl. = Eplerenone.

The plasma concentration of the eplerenones was about 15 to 20 times higher than that of the open ring lactone form.

Pharmacokinetic Parameters Pharmacokinetic Parameter Values (Open Ring Lactone) 10mg (Epl. *) 50mg (Epl.) 100mg (Epl.) 300mg (Epl.) 1000mg (Epl.) AUC (0-96) [(ng / mL) hr] - 142.8 246.8 1065.1 3483.5 C _max (μg / mL) - 36.4 60.4 211.8 521.5 T _max (hours) - 1.0 1.1 1.3 2.5 T _1/2 (hours) - 2.7 2.7 2.8 2.6 Average residence time (hours) - 2.8 3.3 4.2 5.7 Oral Scavenging (L / hr) - 491.3 445.2 299.8 330.7

* Epl. = Eplerenone.

Time after taking (hours) Eplerenone or spironolactone at plasma concentration (ng / mL)  Placebo 10mg (Epl. *) 50mg (Epl.) 100mg (Epl.) 300mg (Epl.) 1000mg (Epl.) 50mg (Spi *) -0.25 5.6 5.2 6.5 6.4 5.7 6.5 5.5 0.5 - 5.5 - - - - - 1.0 5.0 4.6 6.0 5.6 5.5 5.7 5.6 2.0 5.1 4.6 6.1 5.8 5.3 5.4 5.1 3.0 - - 7.1 - - 6.9 - 4.0 4.4 4.3 5.1 4.8 5.2 5.1 4.3 6.0 3.5 3.6 4.4 3.8 4.1 4.5 3.3 8.0 3.4 3.8 4.3 3.8 4.5 4.7 3.5 12.0 3.4 3.2 4.5 4.0 4.3 4.0 3.6 24.0 6.1 5.3 7.4 6.0 6.3 7.2 6.0 48.0 5.1 4.7 6.1 6.0 5.7 6.5 5.2

* See note on Table 24B.

 Collection period Concentrated amount of eplerenone secreted in urine [ng / mL; (mcg)] 10mg (Epl. *) 50mg (Epl.) 100mg (Epl.) 300mg (Epl.) 1000mg (Epl.) -9 to 0 hours 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 to 2 hours 278.0 (21.6) 1252.2 (99.2) 2623.3 (360.2) 9370.1 (677.7) 17858.6 (1482.0) 2 to 4 hours 191.1 (35.8) 1064.6 (175.3) 2305.6 (407.6) 6465.9 (873.7) 24460.3 (5983.3) 4 to 6 hours 107.2 (16.5) 518.3 (60.6) 1157.3 (285.1) 3865.2 (672.6) 13899.7 (4041.5) 6 to 8 hours 63.8 (7.6) 307.3 (30.7) 627.6 (158.8) 2237.8 (337.0) 8782.1 (2083.0) 8 to 10 hours 0 (0) 172.4 (27.6) 362.9 (69.1) 1208.6 (307.9) 4491.0 (1853.9) 10 to 12 hours 0 (0) 72.7 (16.5) 146.6 (44.7) 542.4 (162.4) 2361.1 (1177.2) 12 to 14 hours 0 (0) 23.1 (11.3) 110.3 (26.6) 419.6 (97.4) 3183.7 (892.8) 14 to 16 hours 0 (0) 21.6 (1.5) 36.5 (6.6) 292.6 (52.2) 1405.2 (340.5) 16 to 24 hours 0 (0) 13.1 (4.0) 7.1 (2.7) 126.4 (50.4) 658.0 (366.0) 0 to 24 hours (78.8) (410.6) (1271.4) (2872.3) (17246.6)

See note in Table 24B.

 Collection period Concentration of the amount of open ring lactone secreted in the urine [ng / mL; (mcg)] 10mg (Epl. *) 50mg (Epl.) 100mg (Epl.) 300mg (Epl.) 1000mg (Epl.) -9 to 0 hours 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 to 2 hours 1781.8 (130.9) 9833.2 (689.1) 12079.2 (1079.2) 47865.1 (3357.2) 60184.4 (4589.2) 2 to 4 hours 584.1 (144.5) 6839.0 (801.3) 9309.8 (1355.4) 27970.5 (3923.5) 56341.5 (12603.2) 4 to 6 hours 532.7 (77.3) 3789.4 (404.3) 3712.5 (796.7) 16280.0 (2679.3) 28711.3 (8481.4) 6 to 8 hours 513.3 (50.3) 2776.2 (268.0) 2688.1 (507.1) 11626.0 (1718.3) 27599.7 (5904.1) 8 to 10 hours 130.3 (25.1) 1091.0 (156.3) 1400.6 (246.7) 4425.1 (1053.8) 9952.4 (3566.2) 10 to 12 hours 44.8 (11.0) 461.6 (91.3) 536.5 (154.5) 1965.5 (580.9) 4822.7 (2212.1) 12 to 14 hours 38.8 (7.4) 264.9 (64.0) 431.6 (98.2) 1841.2 (426.7) 5549.0 (1932.3) 14 to 16 hours 26.4 (3.2) 359.9 (33.7) 241.4 (51.1) 1448.3 (259.8) 3877.4 (920.4) 16 to 24 hours 0 (0) 131.0 (42.8) 133.1 (58.8) 721.8 (287.8) 2835.8 (1381.6) 0 to 24 hours (433.3) (2431.2) (4077.9) (12699.9) (39017.9)

* See note on Table 24B.

Total eplerenone in urine (ie, in the form of eplerenone and its open ring lactone) represented about 5% of the dose for all doses administered. The total secretion of urine in total eplerenone occurred almost completely within the first 24 hours after dosing.

 Collection period Log ₁₀ (sodium / potassium) ratio of urine  Placebo 10mg (Epl. *) 50mg (Epl.) 100mg (Epl.) 300mg (Epl.) 1000mg (Epl.) 50mg (Spi *) -9 to 0 hours 0.920 0.918 0.960 0.874 1.026 0.985 1.006 0 to 2 hours 0.675 0.313 0.730 0.463 0.761 0.956 0.657 2 to 4 hours 0.643 0.435 0.901 0.795 1.140 1.313 0.860 4 to 6 hours 0.448 0.401 0.900 0.901 1.231 1.398 0.904 6 to 8 hours 0.590 0.618 0.906 0.970 1.451 1.594 1.023 8 to 10 hours 0.583 0.578 0.769 0.735 1.265 1.451 0.865 10 to 12 hours 0.625 0.614 0.797 0.564 1.123 1.389 0.821

* See note on Table 24B.

Administration of the aldosterone antagonist fludrocortisone resulted in a reduced log ₁₀ (sodium / potassium) ratio of urine. Administration of doses of 50 mg or more of eplerenone reversed the effects of fludrocortisone over 12 hours in response to increased sodium secretion.

 Collection period Urine sodium secretion (mmol)  Placebo 10mg (Epl. *) 50mg (Epl.) 100mg (Epl.) 300mg (Epl.) 1000mg (Epl.) 50mg (Spi *) -9 to 0 hours 28.8 33.4 29.2 25.7 32.8 32.8 29.1 0 to 2 hours 6.5 4.8 6.1 5.6 5.8 9.3 4.1 2 to 4 hours 7.2 7.3 10.3 11.7 15.7 28.1 8.5 4 to 6 hours 5.9 4.3 10.3 15.0 21.9 29.9 9.4 6 to 8 hours 6.0 6.2 9.0 17.9 23.3 36.1 14.8 8 to 10 hours 7.2 7.0 9.4 13.0 25.6 46.8 13.4 10 to 12 hours 8.1 7.1 10.8 7.3 16.1 29.3 8.4 12 to 14 hours 9.6 10.0 11.7 10.2 17.5 44.2 11.5 14 to 16 hours 6.7 4.2 4.0 4.2 8.6 17.0 5.9 16 to 24 hours 5.3 6.8 7.3 6.6 10.0 18.8 11.8

See note in Table 24B.

 Collection period Urine potassium secretion (mmol)  Placebo 10mg (Epl. *) 50mg (Epl.) 100mg (Epl.) 300mg (Epl.) 1000mg (Epl.) 50mg (Spi *) -9 to 0 hours 34.2 36.8 29.9 33.8 29.9 34.1 26.9 0 to 2 hours 10.3 12.8 10.0 13.7 8.4 9.8 7.5 2 to 4 hours 14.9 17.4 13.8 15.1 10.9 13.9 11.8 4 to 6 hours 15.9 13.9 12.7 17.2 12.4 12.2 10.2 6 to 8 hours 12.0 12.9 11.3 15.2 7.9 9.9 13.3 8 to 10 hours 15.5 16.7 15.5 18.2 14.0 16.6 17.9 10 to 12 hours 16.2 15.8 16.3 15.0 12.2 12.1 12.5 12 to 14 hours 20.5 24.9 23.3 21.6 19.3 21.8 20.6 14 to 16 hours 13.1 13.3 9.8 11.4 10.5 9.3 11.4 16 to 24 hours 25.3 27.6 28.3 29.3 21.5 25.7 27.9

See note in Table 24B.

The data demonstrated a primary relationship between eplerenone dose and anti-aldosterone activity. The sodium secretion of urine and the log ₁₀ (sodium / potassium) ratio of urine increased with increasing eplerenone dose.

Example 25 Absorption, Distribution, Metabolism and Release Studies

An open-label, single dose study was adopted to assess the absorption, distribution, metabolism and excretion profiles of a single 100 mg dose of eplerenone oral solution. The pharmacokinetics of the eplerenones in the form of inert open lactone rings were also evaluated.

The study employed eight healthy men. Each subject received a single 100 mg oral dose (0.75 μCi / mg of specific activity) of [14C] eplerenone solution. Plasma, saliva, respiration, urine and stool samples were collected at predetermined intervals and analyzed for sample radioactivity and concentrations in the form of eplerenone and its open lactone ring. Safety was determined based on laboratory tests, indications of life, and the occurrence and type of history event.                 

Subjects fasted overnight prior to dose administration received a single 100 mg oral dose at 0800 hours with a radiolabeled eplerenone aqueous oral solution reconstituted in 80 mL of apple juice / hydroxypropyl-β-cyclodextrin mixture. Subjects drank about 200 mL of water 1, 2 and 3 hours after dosing.

12-lead ECGs were obtained prior to taking the study drug (within one hour) and at 2, 3, 4, and 24 hours after administration of the drug. Body temperature (oral), respiratory rate, and pulse rate and blood pressure (after 3 minutes sitting) were obtained before taking the study drug (within 30 minutes) and at 0.5, 1, 4, and 24 hours after administration. Blood samples were collected at −0.5 (before dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours after dosing. Next cycle: -12 to 0; 0 to 2; 2 to 4; 4 to 8; 8 to 12; 12 to 24; 24 to 48; 72 to 96; 96 to 120; 120 to 144; and 144 to 168 hours Each stool sample began immediately after dosing and continued to be collected for 0800 hours on day 8. In addition, one stool sample was supplied prior to dosing. Collected at 1, 2, 4, 6, 12, and 24 hours Respiratory samples were taken 0.5 hours before dosing and 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours after dosing Collected on.

The data show that the release of eplerenone is not secreted by metabolism and unchanged. The average percentage of doses secreted as urine and fecal total radioactivity were 66.6% and 32.0%, respectively. Most of the urine and fecal radioactivity is due to metabolites and less than 15% due to eplerenone. The average percentage of doses secreted in the form of urinary eplerenone and its open lactone ring was 1.65% and 4.98%, respectively. The average percentage of doses secreted in the form of fecal eplerenone and its open lactone ring were 0.807% and 2.46%, respectively. There were no clinically significant changes in physical investigations, signs of life or clinical test results. There was no serious adverse effect.

There was no detectable concentration of total radioactivity in the breath collected at all time points from all subjects. The average percentage of total radioactivity bound to the plasma protein in the 1.5 hour plasma sample was 49.4%. The average concentration of total radioactivity in this sample was 2.39 μg / mL. When [ ¹⁴ C] eplerenone was immobilized in the control plasma, it was frozen and the percentage of bound eplerenone was 40.4% at a concentration of 14.5 μg / mL.

Average results of the selected tests are shown in Tables 25A, 25B, 25C, and 25D below.

Pharmacokinetic Parameters Total radiation Plasma (+ SEM) Whole blood (+ SEM) Spit (+ SEM) AUC ₀ -inf (ng equivalent / mL) 18400 ± 1200 12800 ± 800 7960 ± 500 C _max (ng equivalent / mL) 2490 ± 110 1770 ± 80 2170 ± 280 T _max (hours) 1.3 ± 0.2 1.1 ± 0.2 0.6 ± 0.1

Time after taking (hours) Plasma concentration (ng / mL) Eplerenon Open lactone ring form -0.5 0 0 0.5 1345.0 63.2 1.0 1617.3 78.0 1.5 1591.3 70.8 2.0 1418.8 59.9 2.5 1258.1 51.0 3.0 1176.3 46.9 4.0 1001.4 41.9 6.0 595.5 23.0 8.0 390.6 13.0 12.0 148.6 1.9 16.0 68.0 0 24.0 17.3 0 36.0 0 0 48.0 0 0 72.0 0 0 96.0 0 0

Plasma Pharmacokinetic Parameters Eplerenon Open lactone ring form AUC _(0-96) (when (ng / mL)) 9537.2 352.2 C _max (μg / mL) 1721.3 82.8 T _max (hours) 1.3 1.1 T _1/2 (hours) _{3.8 3.1} Average residence time (hours) 4.8 3.4 Oral clearance (L / hour) 11.4 306.3

 Collection period Secretion of urine Eplerenon Open lactone ring form Concentration (ng / mL) Sheep (mcg) Concentration (ng / mL) Sheep (mcg) -12 to 0 hours 0 0 0 0 0 to 2 hours 2933.4 457.5 9004.8 1345.3 2 to 4 hours 1635.2 622.0 4235.1 1249.6 4 to 8 hours 1067.0 314.0 4717.1 1349.8 8 to 12 hours 388.9 158.0 1555.7 596.2 12 to 24 hours 99.5 95.7 438.0 400.0 24 to 48 hours 0 0 22.2 38.8 48 to 72 hours 0 0 0 0

More than 90% of the radioactivity of the urine was secreted in the first 24 hours, indicating rapid release of eplanenone and its metabolites. Most of the urine and fecal radioactivity is due to metabolites, pointing to excessive metabolism by the liver.

Example 26 Bioavailability Studies

Bioavailability and safety of each of the five different formulations (each containing 100 mg dose of eplelenone) were evaluated in an open-label, randomized, single dose, five mode crossover study of healthy adults. Subjects were: (i) one Eplerenone 100 mg immediate release (IR) capsule, (ii) one Eplerenone 100 mg immediate release (iR) tablet, and (iii) one with a 50% in vitro dissolution time of 4 hours. Five single doses of 100 mg eplerenone administered in 100 mg adjusted release (R) tablets with Eplerenone 100 mg adjusted release (CR) tablets and (e) one 50% in vitro dissolution time of 6 hours Doses were awarded. A total of 13 subjects began the study with nine subjects, all of whom completed five treatments. Treatment was divided into seven days. Specific pharmaceutical compositions of each formulation are shown in Table 16A.                 

 ingredient Weight percent of tablet / capsules IR capsule (T. * A) IR Tablet (T.B) Two Hour CR Tablet ¹ (TC) Four Hour CR Tablets ² (TD) Six Hour CR Tablet ³ (TE) Eplerenon 25 30 30 30 30 Lactose Monohydrate 57.86 (fast-flow lactose ^TM) 42 40 34 30.5 Microcrystalline Cellulose (AVICEL ^® PH101) 11.34 (AVICEL ^® PH102) 17.5 (7.5% intra ⁴ plus 10% extra ⁴ ) 19.5 19.5 15 Croscarmellose Sodium (Ac-Di-Sol ^TM ) 2 5 - - - Methocel ^® K4M Premium - - 6 12 20 Hydroxypropyl Methylcellulose (Pharmacout ^TM 603) - 3 3 3 3 Sodium lauryl sulfate 0.5 One - - - Talc 2.5 One One One One Magnesium stearate 0.3 0.5 0.5 0.5 0.5 Colloidal silicon dioxide 0.5 - - - - gun 100 100 100 100 100

50% in vitro dissolution time of ¹ 2 hours.

50% in vitro dissolution time of ^{2 to} 4 hours.

³ 6 hours of 50% in vitro dissolution time.

* T. = Processing.

⁴ intra = intragranular; Extra = granular.

Subjects who fasted six hours and did not drink water for one hour prior to each dose were treated with one of five randomized treatment sequences (ABDCE, BCAED, CDEAB, DECBA, and EABDC) at 1, 8, 15, 22, and 29 days. A single oral dose of one of the drugs in this study was awarded. The drug was administered with about 180 mL of water at 0800 hours. Blood samples were collected at −0.5 hours before dosing, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours after dosing. Urine samples were collected and pooled between 0-24 and 24-48 hours post dose. Analysis of isolated plasma and urine for eplanenone and its inactive open lactone ring form was reported in Canada. It was held at Quebec, at Phonics International Life Science. Plasma and urine concentrations in the form of eplerenone and its inert open lactone ring were determined using a proven high performance liquid chromatography ("HPLC") procedure for the inert open lactone ring form. The low limit of urine detection was approximately 50 ng / mL for both the eplerenone and inactive forms. The average results obtained are shown in Tables 26B, 26C, 26D and 26E below. Table 26F illustrates the finely divided eplerenone particle size distribution in microns for some of the preparations used in this example.

Time after taking (hours) Plasma Concentration of Eplerenone (ng / mL) IR capsule IR tablet Two time CR tablets Four hour CR tablets Six Hour CR Tablet -0.5 3.0 0 0 0 0 0.5 939.3 818.2 287.2 144.1 53.5 1.0 1335.8 1413.0 579.2 337.1 176.1 2.0 1560.7 1616.6 973.8 569.0 393.8 3.0 1426.8 1402.1 1111.5 718.3 555.1 4.0 1292.3 1130.2 1109.2 826.1 616.3 6.0 851.3 759.6 933.2 753.2 525.6 8.0 536.9 506.4 690.1 691.7 524.7 10.0 386.3 328.3 540.3 631.1 430.6 12.0 250.9 227.1 417.3 597.5 429.9 16.0 124.3 121.8 229.0 390.1 357.2 24.0 33.2 52.6 81.2 171.0 168.3 36.0 7.1 6.5 17.2 29.4 39.8 48.0 11.8 6.5 6.6 11.4 12.6

 Pharmacokinetic Parameters Eplerenone Plasma Pharmacokinetic Parameters IR capsule IR tablet Two time CR tablets Four hour CR tablets Six Hour CR Tablet AUC _(0-48) [when (ng / mL)] 12042.69 12092.16 11949.27 13263.23 10663.00 AUC _(0-LQC) [at (ng / mL)] 11944.77 11981.35 11706.29 13061.75 10588.93 AUC _(0-∞) [when (ng / mL)] 11224.29 12188.89 12045.98 13402.55 10815.43 C _max (ng / mL) 1704.90 1668.76 1152.65 878.87 709.91 C _max / AUC _(0-LQC) (hr ^-1 ) 0.16 0.17 0.11 0.07 0.08 T _max (hours) 1.84 1.34 3.34 4.56 7.55 T _1/2 (hours) 4.08 4.10 5.17 5.41 6.01 XU _(0-24) (mg) 1.82 1.98 1.81 1.57 1.47 XU _(24-48) (mg) 0.01 0.06 0.00 0.16 0.17 XU _(0-48) (mg) 1.83 2.04 1.81 1.73 1.64

Time after taking (hours) Plasma concentration of open ring lactone (ng / mL) IR capsule IR tablet Two time CR tablets Four hour CR tablets Six Hour CR Tablet -0.5 0 0 0 0 0 0.5 46.5 39.2 9.7 2.9 0.0 1.0 65.4 68.1 24.5 13.3 3.9 2.0 71.1 78.7 43.8 22.9 14.3 3.0 65.0 66.1 47.1 29.5 21.4 4.0 57.5 54.2 47.2 39.3 22.4 6.0 42.3 39.7 46.8 35.5 21.8 8.0 23.8 25.8 33.3 33.4 25.4 10.0 19.5 14.4 26.5 30.2 18.2 12.0 10.6 7.8 20.5 19.0 18.7 16.0 3.9 3.2 10.2 16.4 14.6 24.0 0.0 1.2 1.7 4.9 4.3 36.0 0 0 0 0 1.0 48.0 0 0 0 0 0

 Pharmacokinetic Parameters Open Ring Lactone Plasma Pharmacokinetic Parameters IR capsule IR tablet Two time CR tablets Four hour CR tablets Six Hour CR Tablet AUC _(0-48) [when (ng / mL)] 533.36 502.88 527.62 554.71 402.03 AUC _(0-LQC) [at (ng / mL)] 504.91 475.75 489.86 495.61 356.94 C _max (ng / mL) 86.73 81.81 51.16 44.26 32.59 T _max (hours) 1.89 1.67 4.34 4.79 7.67 XU _(0-24) (mg) 5.94 6.43 6.81 6.42 4.83 XU _(24-48) (mg) 0.16 0.32 0.25 0.70 0.74 XU _(0-48) (mg) 6.10 6.75 7.06 7.12 5.56

D _value Size distribution of finely divided eplerenone particles in microns IR capsule IR tablets, two hours, four hours and six hours CR tablets D ₅ 2 3 D ₁₀ 3 5 D ₅₀ 18 33 D ₇₅ 39 63 D ₉₀ 82 96 D ₉₅ 114 119

Example 27: Effect of Food Research

An open-label randomized, crossover study was adopted to assess the pharmacokinetic profile of eplerenone, and the safety and tolerability of eplerenone under fasting and food feeding conditions. Safety was assessed based on historical events, biomarkers, and clinical laboratory tests. Twelve healthy male subjects were randomized to receive single 100 mg doses of eplerenone on days 1 and 8 immediately after (i) fasting or (ii) high fat breakfast. The subjects were orally administered (dosed) to a single 100 mg dose of the capsule-type eplerenone described in Example 7 with approximately 200-240 mL of water at 0800 hours on days 1 and 8. Randomized subjects who had a high fat breakfast were expected to eat completely within 20 minutes prior to taking. The high fat meal contained approximately 33 g of protein, 75 g of fat, 58 g dml carbohydrate and 1000 calories. Blood samples are collected at -0.5 hours before dosing, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 28, 32, 48 and 72 hours after dosing and with eplerenone and its open lactones. Analysis was made to determine the concentration of the ring form. There was no clinically significant change in the indication of life or physical examination. All history cases were not serious. Average results are shown in Tables 27A and 27B below.

Time after taking (hours) Plasma concentration (ng / mL) Fasting status High Fat Breakfast Eplerenon Open ring lactone form Eplerenon Open ring lactone form -0.5 0 0 0 0 0.5 1010.500 69.163 71.225 2.300 1.0 1562.667 91.208 366.192 17.392 2.0 1393.333 70.600 712.250 36.964 3.0 1174.417 58.833 1038.167 56.742 4.0 955.167 45.042 1239.750 66.817 6.0 586.583 31.773 946.000 51.675 8.0 387.583 18.708 672.833 30.950 12.0 150.850 5.519 282.250 12.708 16.0 68.783 0 130.467 2.540 24.0 17.667 0 39.008 0 28.0 7.617 0 21.733 0 32.0 3.283 0 7.508 0 48.0 0 0 1.908 0 72.0 0 0 0 0

 Pharmacokinetic Parameters Plasma Pharmacokinetic Parameter Values Fasting status High Fat Breakfast Eplerenon Open ring lactone type Eplerenon Open ring lactone type AUC _(0-96) [when (ng / mL)] 9202.063 430.624 10171.631 470.137 C _max (ng / mL) 1634.167 100.158 1334.333 73.858 T _max (hours) 1.292 3.076 3.750 3.198 T _1/2 (hours) 3.369 3.750 3.71 1.125

For the _eplerenones and their open ring lactone forms, high fat meal led to a decrease in C _max , an increase in T _max , and had a minimal or no measurable effect on AUC _0-96 and T _1/2 . The results indicate that high-fat diets have a minimal effect on the extent of eplerenone absorption, but reduce the rate of absorption. Thus, the administration of eplerenone can be made as if the effect of the food has minimal clinical significance regardless of mealtime.

Example 28: Combined Dose Study

The combined oral dose tolerability and pharmacokinetics of several doses of eplerenone is a panel study of 40 healthy male subjects who should be taken in a specific order, resulting in a double-blind, randomized, placebo-adjusted, oral dose (5 groups of 8 subjects) Was evaluated. Study drugs are administered in three specific dose panels, which are to be taken, each containing eplerenone, spironolactone and placebo. A single dose of 100 mg (one 100 mg dose), 300 mg (three 100 mg dose capsules) or 1000 mg dose eplerenone (five 200 mg dose capsules), 1000 mg dose of spironolactone, or placebo was administered daily. 100 mg and 200 mg dose capsules are consistent with those described in Examples 7 and 8, respectively. After a 48 hour interval, study medication was administered once daily for 11 days. Anti-aldosterone activity was determined after fludrocortisan challenge on day 12-13. Plasma pharmacokinetic results are shown in Table 28 below.

Eplerenone Dose: Pharmacokinetic Parameters Pharmacokinetic Parameter Values Eplerenon Open ring shape Single dose Compound capacity Single dose Compound capacity 100mg dose: AUC [when (ng / mL)] 11349 11773 613 663 C _max (ng / mL) 1747 1904 10 129 T _max (hours) 1.8 1.1 1.7 0.7 300mg dose: AUC [when (ng / mL)] 23890 26514 1844 2200 C _max (ng / mL) 3227 3582 292 364 T _max (hours) 2.4 1.8 1.8 1.3 T _1/2 (hours) 4.6 4.6 3.0 3.5 1000 mg dose AUC [when (ng / mL)] 62053 63249 5912 6310 C _max (ng / mL) 6885 7394 782 830 T _max (hours) 2.0 1.4 1.7 1.3 T _1/2 (hours) 8.7 6.2 3.7 4.8

 Eplerenone plasma concentrations were detectable 24 hours post dose for all dose groups. Plasma concentrations of the eplerenones and the mean-dose adjusted AUC values after single or combined doses indicated a poor dose ratio within the 100 mg to 1000 mg dose range. The results for the open ring lactone form were consistent with the dose ratio after single or multiple doses. Overall, there was no significance or dose-related accumulation of eplerenone or its open ring lactone form.

The secretion of total eplerenone in urine (ie, in the form of eplerenone and its open ring lactone) represented about 5% of the dose for all doses administered. The total secretion of urine in total eplerenone occurred almost completely within the first 24 hours after dosing. Eplerenone significantly increased log ₁₀ (sodium / potassium) of urine at a dose of 100 mg to 1000 mg after a single dose administration. However, no increase in the log ₁₀ (sodium / potassium) value of urine was maintained after administration of the combined dose of eplerenone or spironolactone. Serum sodium and potassium concentrations did not change significantly after a single dose of eplerenone, but a temporary decrease in sodium concentration and an increase in potassium concentration were observed after the combined dose administration. Eplerenones produced dose-related increases in mean plasma renin (activity and total) levels and serum aldosterone levels, but did not show all consistent, sustained or dose-related effects on most serum sex hormone and thyroid profiles. .

Example 29 Hypertension Treatment Studies

The safety and efficacy of the dose range of eplerenone in treating hypertension compared to placebo was assessed in a combination-center, randomized, double-blind, placebo-lead-, comparable group study. Spironolactone 50 mg BID was included as an active reference drug. 417 patients have the following eight treatments: (iii) placebo BID; (Ii) eplerenone 50 mg QD; (Iii) Eplerenone 100 mg QD; (Iii) Eplerenone 400 mg QD; (Iii) Eplerenone 25 mg BID; (Iii) eplerenone 50 mg BID; (Iii) Eplerenone 200 mg BID; And (iii) spironolactone 50 mg BID. The first efficacy variable was the change in cuff dilator blood pressure (ΔDBP; sitting) measured through plasma levels after 8 weeks of double blind treatment. The second variables measured were changes through cuff contraction blood pressure (ΔSBP; sitting), changes in 24 hour average diastolol blood pressure (ΔDBP), and changes in 24 hour average contractile blood pressure (ΔSBP). The first and second efficacy variables were analyzed to compare the BID to QD dose regimen for each group of eplerenone doses and for both the fullerenone and spironolactone versus placebo. Changes in plasma renin and serum aldosterone at 8 weeks after dosing were also analyzed as a second measure of efficacy.

All eplerenone doses lowered cuff diastolic and systolic blood pressure from baseline 8 weeks after treatment compared to placebo. As the diastolic and export blood pressure decreased, it was observed to increase the dose of eplerenone. In general, the reduction in blood pressure equivalent was associated with the QD and BID dose regimens. However, there is a tendency for a decrease in the BID-dose regimen to be greater. Similar changes were observed within 24 hours through outpatient blood pressure. Throughout the course of the study, the mean change in pulse from baseline was minimal in all treatment groups with the largest mean increase and decrease in heart rate at +2 pulse / min and -1.8 pulse / min, respectively. Consistent with the aldosterone receptor antagonist, there was an increase in both total and active renin levels as well as an increase in aldosterone in both the eplerenone and spironolactone treatment groups compared to placebo. Safety was assessed by comparing hematology and biochemistry laboratory tests for treatment versus placebo groups, as a result of history, suspension, and urine analysis.

The increase in potassium and the decrease in sodium in all eplerenone treatment groups were small but consistent. Within the eplerenone treatment group there was a decrease in BUN, increased uric acid levels, and decreased urine pH compared to placebo. Each Eplereron regimen was well tolerated by subjects. No adverse effects were observed at 1000 mg, highest dose.

Specific pharmaceutical compositions of each eplerenone capsule are described in Examples 5, 6, 7, and 8. Placebo was a conventional capsule containing lactose. The spironolactone used in this study was obtained from Sear Canata (Oakville, Ontario).

Average results obtained from the test subjects are shown in Tables 29A and 29B below.

 Treatment regime Primary efficacy variable Second efficacy variable △ Through DBP (mmHG, sitting) △ SBP through (mmHg, sitting) 24 hours average △ DBP (mmHg) 24 hours average △ SBP (mmHg) Placebo -1.0 2.0 0.6 0.0 Eplerenone 50mg QD -4.4 -4.6 -4.8 -7.1 Eplerenone 100mg QD -4.5 -8.0 -6.1 -9.7 Eplerenone 400mg QD -8.9 -14.1 -7.6 -13.0 Eplerenone 25mg BID -4.5 -8.9 -3.9 -7.4 Eplerenone 50mg BID -7.8 -11.8 -7.2 -12.6 Eplerenone 200mg BID -9.4 -15.8 -9.3 -15.9 Spironolactone 50mg BID -9.5 -17.6 -8.9 -15.7

An average increase in diastolic blood pressure of at least about 5% was observed throughout the interval between about 12 and 24 days after administration of the study drug.

 Treatment regimen Plasma Lenin Activity: Average Change from Baseline (mU / L) Serum aldosterone: mean change from baseline (ng / dL) Placebo 2.2 1.0 Eplerenone 50mg QD 2.9 6.0 Eplerenone 100mg QD 13.9 10.5 Eplerenone 400mg QD 21.2 19.2 Eplerenone 25mg BID 1.2 7.3 Eplerenone 50mg BID 15.0 10.0 Eplerenone 200mg BID 32.0 32.8 Spironolactone 50mg BID 13.3 19.2

An average increase in plasma renin concentration of at least about 10% was observed throughout the interval of about 12 to 24 hours after administration of the drug. An average increase in plasma aldosterone concentration of at least about 50% was observed throughout the interval of about 12 to 24 hours after administration of the drug.

Example 30 Effect of Eplerenone Particle Size

The effect of the particle size of the eplerenone initiator used in the pharmaceutical composition on the eplelenone plasma concentration and relative bioavailability was studied in a dog model. Four healthy female beagle dogs of about 8-12 kg were administered one immediate release (IR) capsule into the gastrointestinal tract, including the formulations described in Table 30A below, and about 10 mL of water.

ingredient Weight percent of tablet Amount (mg) Eplerenon 50.00 200.00 Lactose, Fast-Flo ^TM Hydrus 36.95 147.80 Microcrystalline Cellulose (AVICEL ^® PH102) 7.25 29.00 Sodium lauryl sulfate 0.50 2.00 Croscarmellose sodium 2.00 8.00 Talc 2.50 10.00 Colloidal silicon dioxide 0.50 2.00 Magnesium stearate 0.30 1.20 gun 100.00 400.00 Capsule, Size # 0, White O Park 1 capsule

Dogs were not fed for 15-20 hours prior to dosing of the capsules and again for at least 4 hours after dose administration. Blood samples (approximately 3 mL) were collected by venipuncture in refrigerated tubes containing heparin at 0, 0.5, 1, 2, 3, 4, 6, 8 and 24 hours after dose administration. Blood samples were immediately placed on ice. Separation of the plasma from the blood sample was completed after about 15 minutes of centrifugation. The resulting plasma sample was frozen at about −20 ° C. and stored until analysis. Analysis was performed using LC / MS / MS procedure.

The study was conducted using four identical dogs for the same three formulations except for the particle size of the eplerenone initiator. Three formulations were used to evaluate the used eplerenone initiators each having a D ₉₀ particle size of less than about 212 microns, up to about 86 microns, up to about 36 microns (ie with at least 90% particles). . A washout period of at least 5 days was allowed between administrations of each formulation. Reducing the D ₉₀ particle size of the eplerenone initiator from about 21 microns to about 86 microns or less increased the relative bioavailability to 100% of this. Average results are shown in Tables 30B and 30C below.

 Hour Serum Eplerenone Concentration (µg / mL) D ₉₀ = 212 microns D ₉₀ = 86 microns D ₉₀ = 36 microns 0 0 0 0 0.5 1.83 3.65 1.99 1.0 2.40 6.18 5.86 2.0 3.77 6.89 6.77 3.0 2.85 5.70 6.60 4.0 2.61 4.39 5.56 6.0 1.63 3.11 3.31 8.0 1.10 1.90 2.09 24.0 0.0252 0.032 0.0706

 Pharmacokinetic Parameters Pharmacokinetic Parameter Values D ₉₀ = 212 microns D ₉₀ = 86 microns D ₉₀ = 36 microns C _max (μg / mL) 3.98 7.02 7.39 T _max (hours) 1.50 1.75 2.25 AUC [when (μg / mL)] 26.6 49.2 53.1 Relative Bioavailability (%) 53.25 100 107.9

Justice

The term "carrier" refers to a substance included in a pharmaceutical composition to impart certain desired properties. For example, in the case of tablets, a carrier material can be added to moderate dissolution rate, mask bad taste, or improve the appearance of the tablet.                 

The term "substrate" or "substrate system" means the binding of all carrier materials of a given formulation to which the active drug is bound.

The term "AUC _(0-48) " means the area under the plasma concentration-time curve from t = 0 to t = 48 in [ng / mL) time units determined using the formulation method.

The term “AUC _(0-LQC) ” refers to the area under the plasma concentration-time curve from t = 0 in units of [ng / mL] determined using the formulation method to a final quantifiable concentration (“LQC”). it means.

"C _max " means the maximum observed concentration.

"T _max " means the time when C _max occurs.

“T _1/2 ” means the final half-life, in units of time, determined through a simple linear regression of the natural log (ln) concentration versus time for a data point in the 'terminal phase' of the concentration-time curve. T _1/2 is calculated by ln (2) / (− β).

“AUC _(0-∞) ” is calculated by AUC _(0-LQC) + LQC / (− β), where LQC is the final quantifiable plasma concentration and β is the slope obtained from the calculation of T _1/2 .

"C _max / AUC _(0-LQC) " means absorption rate.

"XU _(0-τ) " is the urinary eplerenone (or inactive open lactone) calculated as the urine drug concentration increased by urine volume during each collection period (0-24, 24-48 and 0-48 hours). The total amount of eplerenone in the form of a ring).

"MRT" is the mean residence time calculated as null below the moment slope (AUMC _(0-96) divided by AUC _(0-96) .

"CL / F" means clear (oral) erasure calculated as (1000 x dose mg) / AUC _(0-96) .

Various changes may be made in the above formulations and methods without departing from the scope of the invention, and all materials included in the detailed description of the invention are to be interpreted as illustrative and not restrictive. All patent documents listed herein are incorporated by reference.

Claims (70)

A pharmaceutical composition, characterized in that it comprises 10 mg to 1000 mg of finely divided eplerenone and a pharmaceutically acceptable carrier material such that at least 90% has a size of 25 to 400 microns. The method of claim 1, The composition is a pharmaceutical composition, characterized in that it comprises 20mg to 400mg finely divided eplerenone. The method of claim 1, The composition is a pharmaceutical composition, characterized in that it comprises 25mg to 150mg finely divided eplerenone. The method of claim 1, 24 to 35% by weight of finely divided eplerenone; 25 to 45% by weight of lactose; 10-25% microcrystalline cellulose; And A pharmaceutical composition comprising 5 to 50% by weight of hydroxypropyl methylcellulose. The method of claim 1, Wherein said carrier material is cellulosic and said cellulosic carrier material is selected from the group consisting of purified cellulose, microcrystalline cellulose, alkyl cellulose and derivatives and salts thereof. The method of claim 1, A pharmaceutical composition comprising one or more pharmaceutically acceptable carriers selected from the group consisting of diluents, binders, disintegrants, wetting agents, glidants and semi-binders or glidants. The method of claim 6, (a) the binder is 0.5 to 25% by weight of the total composition, (b) the diluent is from 5 to 99% by weight of the total composition (c) the disintegrant is from 0.5 to 30% by weight of the total composition (d) the wetting agent is from 0.1 to 15% by weight of the total composition weight (e) the lubricant is 0.1 to 10% by weight of the total composition weight (f) The semi-binder or glidant is 0.25-10% by weight of the total composition. The method of claim 7, wherein (a) The binder is acacia, tragacanth, sucrose, gelatin, glucose, starch, cellulose, alginic acid, alginate, magnesium aluminum silicate, polyethylene glycol, gum, polysaccharide acid, bentonite, polyvinylpyrrolidone, polymetha Selected from the group consisting of acrylate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose and pregelatinized starch, (b) The diluent is lactose, starch, mannitol, sorbitol, dextrose, microcrystalline cellulose, dibasic calcium phosphate, sucrose-based diluent, powdered sugar, monobasic calcium sulfate monohydrate, calcium sulfate dihydrate, calcium lactate Trihydrate, textrate, inositol, hydrolyzed cereal solids, amylose, powdered cellulose, calcium carbonate, glycine and bentonite, (c) the disintegrant is selected from the group consisting of starch, sodium starch glycorate, clay, cellulose, alginate, pregelatinized corn starch, crospovidone and gums, (d) the wetting agent is oleic acid, glyceryl monostearate, sorbitan mono-oleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan mono-oleate, polyoxyethylene sorbitan monolaurate , Sodium oleate and sodium lauryl sulfate, (e) The glidants are glyceryl behenate, stearate, stearic acid, hydrogenated vegetable oil, talc, wax, stearowet, boric acid, sodium benzoate, sodium acetate, sodium chloride, DL-leucine, polyethylene glycol, oleic acid Selected from the group consisting of sodium, sodium lauryl sulfate and magnesium lauryl sulfate, (f) The semi-binder or glidant is selected from the group consisting of talc, corn starch, DL-leucine, sodium lauryl sulfate and stearic acid metal salt. The method of claim 6, (a) 1 to 90 weight percent of micronized eplerenone; (b) 5-90% by weight of lactose; (c) 5-90% microcrystalline cellulose; (d) 0.5 to 10 weight percent hydroxypropyl methylcellulose; And (e) 2 to 6% by weight of croscarmellose sodium; a pharmaceutical composition comprising a. The method of claim 1, Pharmaceutical composition, characterized in that in unit dosage form. The method of claim 10, The unit dosage form is a pharmaceutical composition, characterized in that the unit dosage tablet or capsule form. The method of claim 11, Wherein said unit dosage tablet or capsule form has 25 mg, 50 mg or 100 mg of eplerenone. The method of claim 11, The unit dosage tablet or capsule form is a pharmaceutical composition, characterized in that oral administration once or twice a day. The method of claim 10, Wherein said composition is directly encapsulated or compressed directly into one or more tablets. The method of claim 10, Wherein said composition is wet granulated and encapsulated or compressed into one or more tablets. The method of claim 10, Wherein said composition is dry granulated and encapsulated or compressed into one or more tablets. The method of claim 1, A pharmaceutical composition, characterized in that at least 90% of the finely divided eplerenone particles used in the preparation of the pharmaceutical composition have a size of 200 microns or less. The method of claim 17, A pharmaceutical composition, characterized in that at least 90% of the finely divided eplerenone particles used in the preparation of the pharmaceutical composition have a size of 150 microns or less. The method of claim 17, A pharmaceutical composition, characterized in that at least 90% of the eplerenones used in the preparation of the pharmaceutical composition have a size of 30 to 150 microns. The method of claim 17, A pharmaceutical composition, characterized in that at least 90% of the eplerenone particles used in the preparation of the pharmaceutical composition have a size of 30 to 50 microns. The method of claim 1, A pharmaceutical composition comprising epulenone and β-cyclodextrin micronized in a liquid dosage form. The method of claim 1, A pharmaceutical composition for treating a condition or disorder wherein the pharmaceutical composition is indicated for the treatment of an aldosterone receptor blocker, the composition comprising orally administering to a patient in need of such treatment. The method of claim 22, The condition or disorder is a pharmaceutical composition, characterized in that heart disease, hypertension, liver failure and myocardial infarction. A pharmaceutical composition for the treatment or prophylaxis of an aldosterone-mediated condition or disorder comprising at least 90% finely divided eplelenone and a cellulosic carrier so as to have a size of 25 to 400 microns. Wet granulating the finely divided eplerenone and at least one carrier material such that at least 90% has a size of 25 to 400 microns to form a wet granulated mixture; And Preparing a pharmaceutical composition in oral dosage form in a wet granulated mixture. The method of claim 25, Wherein said pharmaceutical composition is prepared in an oral unit dosage form comprising 25 mg, 50 mg or 100 mg of finely divided eplerenone. The method of claim 1, A pharmaceutical composition characterized by providing a therapeutic effect as an aldosterone receptor blocker over an interval of 12 to 24 hours after ingestion. The method of claim 1, 50% or more of the composition of the composition is released in 20 minutes in 0.1N hydrochloric acid in vitro. The method of claim 1, Wherein said composition causes an average increase in serum renin concentration in the human body over an interval of 12 to 24 hours after ingestion of at least 10% or at least 50% of the composition. The method of claim 1, Wherein said composition causes an average decrease in diastolic blood pressure in the human body over an interval of 12 to 24 hours after ingestion of at least 5% of the composition. The method of claim 1, Wherein said composition is in oral dosage form wherein at least 50% of the eplerenone in the composition is released within 1.5%, 3.5 hours, or 5.5 hours in 1% sodium dodecyl sulfate (SDS) in vitro. delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete

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